Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities [, , ]. Tumor necrosis factor (TNF) (also known as TNF-alpha or cachectin) is a monocyte-derived cytotoxin that has been implicated in tumour regression, septic shock and cachexia [, ]. The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine []. A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers []. Both the mature protein and a partially-processed form of the hormone are secreted after cleavage of the propeptide [].There are a number of different families of TNF, but all these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors.
TNF receptor-associated factor 6 (TRAF6) regulates a diverse array of processes, including adaptive immunity, innate immunity, bone metabolism and tissue development. It is a unique member of the TRAF family of adaptor proteins in that it is involved in both the TNF receptor superfamily and the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily signal transduction pathways [, , , ]. TRAF6 possesses ubiquitin ligase activity that controls the activation of IKK and NF-kappaB [, ]. TRAF6 contains a RING finger domain, five zinc finger domains, and a TRAF domain.
TNF receptor-associated factor 5 (TRAF5) is an adapter protein and signal transducer that links members of the tumor necrosis factor receptor family to different signaling pathways by association with the receptor cytoplasmic domain and kinases. TRAF5 mediates activation of NF-kappa-B and probably JNK [, , , ]. TRAF5 contains a RING finger domain, five zinc finger domains, and a TRAF domain.
TNF receptor-associated factor 4 (TRAF4) is an adapter protein and signal transducer that links members of the tumor necrosis factor receptor (TNFR) family to different signaling pathways. TRAF4 plays a role in the activation of NF-kappa-B and JNK, and in the regulation of cell survival and apoptosis. It regulates activation of NF-kappa-B in response to signaling through Toll-like receptors. TRAF4 modulates TRAF6 functions [, , , , , ]. In mouse, it has been shown to be required for normal skeleton development, and for normal development of the respiratory tract []. TRAF4 contains a RING finger domain, seven zinc finger domains, and a TRAF domain.
TNF receptor-associated factor 2 (TRAF2) regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis [, ].TRAF2 is heavily regulated by ubiquitin signals. It has E3 ubiquitin-protein ligase activity and promotes K63-linked ubiquitination of target proteins. Alternatively, TRAF2 may be required for recruiting other E3 ligases, such as A20, to help processing and turnover. Furthermore, TRAF2 is regulated by both K63 and K48 type ubiquitin chains. K63 linkage may be mediated by TRAF2 auto-ubiquitination, and is required for TRAF2 activation. c-IAPl and Siah2 are known E3 ligases that can K48-ubiquitinate TRAF2 to target it for proteasome-dependent degradation [, , ]. TRAF2 contains a RING finger domain, five zinc finger domains, and a TRAF domain.
TNF receptor-associated factor 1 (TRAF1) plays a role in the regulation of cell survival and apoptosis []. TRAF1 is unique among TRAF proteins in that it lacks a RING domain found in the N-terminal regions of other TRAFs []. The heterotrimer formed by TRAF1 and TRAF2 is part of a E3 ubiquitin-protein ligase complex that promotes ubiquitination of target proteins, such as MAP3K14 [, ].TRAF1 is unique among the TRAFs in that it lacks a RING domain, which is critical for the activation of nuclear factor-kappaB and Jun NH2-terminal kinase. Studies on TRAF1-deficient mice suggest that TRAF1 has a negative regulatory role in TNFR-mediated signaling events []. TRAF1 contains one zinc finger and one TRAF domain.
The tumour necrosis factor (TNF) receptor associated factors (TRAFs) are major signal transducers for the TNF receptor (TNFR) superfamily and the interleukin-1 receptor/Toll-like receptor superfamily in mammals []. TRAFs constitute a family of genetically conserved adapter proteinsfound in mammals (TRAF1-6) as well as in other multicellular organisms such as Drosophila [], Caenorhabditis elegans []. TRAF2 is the prototypical member of the family. Mammalian TRAF1 and TRAF2 were the first members initially identified by their association with TNFR2. The TRAF1/TRAF2 and TRAF3/TRAF5 gene pairs may have arisen from recent independent gene duplications and to share a common ancestral gene. TRAF4 and TRAF6 precursor genes may have arisen earlier during evolution, with the divergence of the TRAF6 precursor occurring earliest of all. Except TRAF1, this PIRSF has a general domain architecture containing one N-terminal RING finger, a variable number of middle region of TRAF-type zinc finger and C2H2 type of zinc finger, and one C-terminal MATH domain. TRAF1 is unique in the family in that it lacks the N-terminal RING and zinc-finger domains []. This has rendered TRAF1 unable to promote TNF receptor signalling and act as a "dominant negative"TRAF []. Also TRAF1 is a substrate for caspases activated by TNF family death receptors []. The larger C-terminal cleaved fragment can bind to and sequester TRAF2 from TNFR1 complex, therefore modulating TNF induced NFkB activation []. A wide range of biological functions, such as adaptive and innate immunity, embryonic development, stress response and bone metabolism, are mediated by TRAFs through the induction of cell survival, proliferation, differentiation and death. TRAFs are functionally divergent from a perspective of both upstream and downstream TRAF signal transduction pathways and of signalling-dependent regulation of TRAF trafficking. Each TRAF protein interacts with and mediates the signal transduction of multiple receptors, and in turn each receptor utilises multiple TRAFs for specific functions []. About 40 interaction partners of TRAF have been described thus far, including receptors, kinases, regulators and adaptor proteins.TRAF proteins can be recruited to and activated by ligand-engaged receptors in least three distinct ways []. 1) Members of the TNFR superfamily that do not contain intracellular death domains, such as TNFR2 and CD40, recruit TRAFs directly via short sequences in their intracellular tails []. 2) Those that contain an intracellular death domain, such as TNFR1, first recruit an adapter protein, TRADD, via a death-domain-death-domain interaction, which then serves as a central platform of the TNFR1 signalling complex, which assembles TRAF2 and RIP for survival signalling, and FADD and caspase-8 for the induction of apoptosis. 3) Members of the IL-1R/TLR superfamily contain a protein interaction module known as the TIR domain, which recruits, sequentially, MyD88, a TIR domain and death domain containing protein, and IRAKs, adapter Ser/Thr kinases with death domains. IRAKs in turn associate with TRAF6 to elicit signalling by IL-1 and pathogenic components such as LPS. A common mechanism for the membrane-proximal event in TRAF signalling has been revealed by the conserved trimeric association in the crystal structure of the TRAF domain of TRAF2 [].
This domain is found in TNF receptor-associated factor 1 and 2 (TRAF1 and TRAF2), where it binds to Baculoviral IAP repeat-containing protein 3 (BIRC3) (cIAP2) [].
Tumor necrosis factor (TNF) receptor associated factor 3 (TRAF3) is a highly versatile regulator that positively controls type I interferon production, but negatively regulates mitogen-activated protein (MAP) kinase activation and non-canonical nuclear factor-kB signalling []. It is a critical regulator of both innate and adaptive immune responses []. TRAF3 plays a role in the regulation of B-cell survival [], in the regulation of antiviral responses [], and in T-cell dependent immune responses []. It is required for normal antibody isotype switching from IgM to IgG []. Differences in the ubiquitination of TRAF3 are the key to the selective production of type I interferons versus proinflammatory cytokines [].
The members of tumor necrosis factor receptor (TNFR) superfamily have been designated as the "guardians of the immune system"due to their roles in immune cell proliferation, differentiation, activation, and death (apoptosis). RELT (receptor expressed in lymphoid tissues) is a member of the TNFR superfamily. The messenger RNA of RELT is especially abundant in hematologic tissues such as spleen, lymph node, and peripheral blood leukocytes as well as in leukemias and lymphomas. RELT is able to activate the NF-kappaB pathway and selectively binds tumor necrosis factor receptor-associated factor 1 []. RELT like proteins 1 and 2 (RELL1 and RELL2) are two RELT homologues that bind to RELT. The expression of RELL1 at the mRNA level is ubiquitous, whereas expression of RELL2 mRNA is more restricted to particular tissues [].
This family consists of several Orthopoxvirus proteins of around 185 resides in length. Members of this family seem to be exclusive to Vaccinia virus, Camelpox virus and Cowpox virus (CPV). Some family members are annotated as being C8 proteins but their function is unknown.
The tumour necrosis factor (TNF) receptor associated factors (TRAFs) are major signal transducers for the TNF receptor (TNFR) superfamily and the interleukin-1 receptor/Toll-like receptor superfamily in mammals []. TRAFs constitute a family of genetically conserved adapter proteins found in mammals (TRAF1-6) as well as in other multicellular organisms such as Drosophila [], Caenorhabditis elegans []. TRAF2 is the prototypical member of the family. Mammalian TRAF1 and TRAF2 were the first members initially identified by their association with TNFR2. The TRAF1/TRAF2 and TRAF3/TRAF5 gene pairs may have arisen from recent independent gene duplications and to share a common ancestral gene. TRAF4 and TRAF6 precursor genes may have arisen earlier during evolution, with the divergence of the TRAF6 precursor occurring earliest of all. Except TRAF1, this PIRSF has a general domain architecture containing one N-terminal RING finger, a variable number of middle region of TRAF-type zinc finger and C2H2 type of zinc finger, and one C-terminal MATH domain. TRAF1 is unique in the family in that it lacks the N-terminal RING and zinc-finger domains []. This has rendered TRAF1 unable to promote TNF receptor signalling and act as a "dominant negative"TRAF []. Also TRAF1 is a substrate for caspases activated by TNF family death receptors []. The larger C-terminal cleaved fragment can bind to and sequester TRAF2 from TNFR1 complex, therefore modulating TNF induced NFkB activation []. A wide range of biological functions, such as adaptive and innate immunity, embryonic development, stress response and bone metabolism, are mediated by TRAFs through the induction of cell survival, proliferation, differentiation and death. TRAFs are functionally divergent from a perspective of both upstream and downstream TRAF signal transduction pathways and of signalling-dependent regulation of TRAF trafficking. Each TRAF protein interacts with and mediates the signal transduction of multiple receptors, and in turn each receptor utilises multiple TRAFs for specific functions []. About 40 interaction partners of TRAF have been described thus far, including receptors, kinases, regulators and adaptor proteins.TRAF proteins can be recruited to and activated by ligand-engaged receptors in least three distinct ways []. 1) Members of the TNFR superfamily that do not contain intracellular death domains, such as TNFR2 and CD40, recruit TRAFs directly via short sequences in their intracellular tails []. 2) Those that contain an intracellular death domain, such as TNFR1, first recruit an adapter protein, TRADD, via a death-domain-death-domain interaction, which then serves as a central platform of the TNFR1 signalling complex, which assembles TRAF2 and RIP for survival signalling, and FADD and caspase-8 for the induction of apoptosis. 3) Members of the IL-1R/TLR superfamily contain a protein interaction module known as the TIR domain, which recruits, sequentially, MyD88, a TIR domain and death domain containing protein, and IRAKs, adapter Ser/Thr kinases with death domains. IRAKs in turn associate with TRAF6 to elicit signalling by IL-1 and pathogenic components such as LPS. A common mechanism for the membrane-proximal event in TRAF signalling has been revealed by the conserved trimeric association in the crystal structure of the TRAF domain of TRAF2 [].This entry represents the TNF receptor associated factors found in metazoa.
This domain is the second of three zinc fingers of Homo sapiens TNF receptor associated factor 6 (TRAF6). TRAF6 mediates Lys63 (K63)-linked polyubiquitination for Necrosis Factor-kappaB activation. The first three residues and the last Cys of finger 1 form a classical type I β-turn [].
TNF receptor-associated factor 6 (TRAF6) regulates a diverse array of processes, including adaptive immunity, innate immunity, bone metabolism and tissue development. It is a unique member of the TRAF family of adaptor proteins in that it is involved in both the TNF receptor superfamily and the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily signal transduction pathways [, , , ]. TRAF6 possesses ubiquitin ligase activity that controls the activation of IKK and NF-kappaB [, ]. TRAF6 contains a RING finger domain, five zinc finger domains, and a TRAF domain.The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded β-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors [, ].
TNF receptor-associated factor 5 (TRAF5) is an adapter protein and signal transducer that links members of the tumor necrosis factor receptor family to different signaling pathways by association with the receptor cytoplasmic domain and kinases. TRAF5 mediates activation of NF-kappa-B and probably JNK [, , , ]. TRAF5 contains a RING finger domain, five zinc finger domains, and a TRAF domain.The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded β-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors [, ].
TNF receptor-associated factor 2 (TRAF2) regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis [, ].TRAF2 is heavily regulated by ubiquitin signals. It has E3 ubiquitin-protein ligase activity and promotes K63-linked ubiquitination of target proteins. Alternatively, TRAF2 may be required for recruiting other E3 ligases, such as A20, to help processing and turnover. Furthermore, TRAF2 is regulated by both K63 and K48 type ubiquitin chains. K63 linkage may be mediated by TRAF2 auto-ubiquitination, and is required for TRAF2 activation. c-IAPl and Siah2 are known E3 ligases that can K48-ubiquitinate TRAF2 to target it for proteasome-dependent degradation [, , ]. TRAF2 contains a RING finger domain, five zinc finger domains, and a TRAF domain. The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded β-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors [, ].
TNF receptor-associated factor 1 (TRAF1) plays a role in the regulation of cell survival and apoptosis []. TRAF1 is unique among TRAF proteins in that it lacks a RING domain found in the N-terminal regions of other TRAFs []. The heterotrimer formed by TRAF1 and TRAF2 is part of a E3 ubiquitin-protein ligase complex that promotes ubiquitination of target proteins, such as MAP3K14 [, ].TRAF1 is unique among the TRAFs in that it lacks a RING domain, which is critical for the activation of nuclear factor-kappaB and Jun NH2-terminal kinase. Studies on TRAF1-deficient mice suggest that TRAF1 has a negative regulatory role in TNFR-mediated signaling events []. TRAF1 contains one zinc finger and one TRAF domain.The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded β-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors [, ].
TNF receptor-associated factor 4 (TRAF4) is an adapter protein and signal transducer that links members of the tumor necrosis factor receptor (TNFR) family to different signaling pathways. TRAF4 plays a role in the activation of NF-kappa-B and JNK, and in the regulation of cell survival and apoptosis. It regulates activation of NF-kappa-B in response to signaling through Toll-like receptors. TRAF4 modulates TRAF6 functions [, , , , , ]. In mouse, it has been shown to be required for normal skeleton development, and for normal development of the respiratory tract []. TRAF4 contains a RING finger domain, seven zinc finger domains, and a TRAF domain.The TRAF domain can be divided into a more divergent N-terminal alpha helical region (TRAF-N), and a highly conserved C-terminal MATH subdomain (TRAF-C) with an eight-stranded β-sandwich structure. TRAF-N mediates trimerization while TRAF-C interacts with receptors [, ].
This domain is found in Chlamydia virulence proteins which are thought to be required for growth within mammalian cells []. The C-terminal domain shows distant homology to the TNF superfamily [].
Endosome-associated-trafficking regulator 1 (ENTR1; also known as serologically defined colon cancer antigen 3, SDCCAG3) is important for protein trafficking and presentation of TNF receptor 1 on the cell surface []. It is also involved in the regulation of cytokinesis []and the formation of cilia [].
CD70 is a ligand of CD27 and is a TNF related transmembrane protein induced upon activation on T and B cells []. The CD27/CD70 interaction plays a key role in T dependent B cell responses and is responsible for plasma cell differentiation []. The CD27/CD70 pathway has been shown to contribute to the pathophysiology of autoimmunity [].
The tumour necrosis factor (TNF)-like domains are found in both TNF and C1q protein families. Structurally these domains self-associate to make a compact bell-shaped homotrimer, each monomer being composed of an anti-parallel β-sheet sandwich with a jellyroll topology. Both TNF and C1q family members can be expressed as soluble plasma proteins or as type II membrane-bound proteins.TNF family members bind extracellularly to cysteine-rich receptors, thereby inducing a clustering of the receptors, which subsequently triggers the intracellular apoptotic cascade. The TNF proteins are important mediators in inflammation, immune responses and cytotoxicity through their interaction with the TNF-R55 and the TNF-R75 cell-surface receptors []. Other TNF family members include the CD40 ligand (C-terminal TNF-like domain) which is involved in the immune response via the CD40 receptor []; TRAIL, which selectively induces apoptosis in tumour cells via DR4 and DR5 receptors []; the RANK ligand (TNFSF11), which triggers osteoclastogenesis via the RANK receptor []; and TALL-1 (soluble domain), which is involved in the immune response via the TACI, BCMA, and BAFF-R receptors [].C1q proteins also contain TNF-like domains. C1q family members include the Adiponectin/ACRP30 (C-terminal TNF-like domain), which regulates metabolism and energy homeostasis [], and NC1 (non-collagenous domain 1), the C-terminal TNF-like domain of collagen X, which is crucial for collagen X assembly in bone tissue [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residuesarranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptors 11A and 11B mediate the effects of receptor activator for NF-kappa-B ligand (RANKL), an essential osteoclast regulatory factor. The receptors have opposing effects -activation of TNF receptor 11A by RANKL promotes osteoclast differentiation [], while TNF receptor 11B acts as a soluble decoy receptor for the ligand, thus inhibiting differentiation []. TNF receptor 11B (also known as osteoprotegerin (OPG)) is a secreted protein that contains two death domains within its C-terminal region. Mutations in the TNF receptor 11B gene are associated with the autosomal recessive osteopathy juvenile Paget disease []. The receptor may also be involved in vascular calcification, and high expression levels in serum are a risk factor for the progression of atherosclerosis and the onset of cardiovascular disease [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain - a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptors 11A and 11B mediate the effects of receptor activator for NF-kappa-B ligand (RANKL), an essential osteoclast regulatory factor. The receptors have opposing effects - activation of TNF receptor 11A by RANKL promotes osteoclast differentiation [], while TNF receptor 11B acts as a soluble decoy receptor for the ligand, thus inhibiting differentiation []. Mutations in the TNF receptor 11A gene have been implicated in a range of bone disorders, such as expansile osteolysis, osteopetrosis, and Paget disease of bone. The receptor also has a role in immune function, vascular disease and mammary gland development [].
TNFSF18, also known as GITRL (glucocorticoid-induced TNF receptor ligand), binds to its receptor GITR on both effector and regulatory T cells and generates positive costimulatory signals []. GITR is also activated by a GITR ligand called SECTM1A []. The costimulatory effect of GITR activation in T cells has been shown to increase T cell expansion and cytokine production, exacerbate autoimmune/inflammatory diseases, favour tumour rejection, perform viral and parasite clearance, and potentiate immune/inflammatory responses [, ].
Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B, also known as TNFR2, type 2 TNFR, TNFBR, TNFR80, TNF-R75, TNF-R-II, p75, CD120b) binds TNF-alpha, but lacks the death domain (DD) that is associated with the cytoplasmic domain of TNFRSF1A (TNFR1) []. It is inducible and expressed exclusively by oligodendrocytes, astrocytes, T cells, thymocytes, myocytes, endothelial cells, and in human mesenchymal stem cells []. TNFRSF1B protects oligodendrocyte progenitor cells (OLGs) against oxidative stress, and induces the up-regulation of cell survival genes []. While pro-inflammatory and pathogen-clearing activities of TNF are mediated mainly through activation of TNFRSF1A, a strong activator of NF-kappaB, TNFRSF1B is more responsible for suppression of inflammation []. Although the affinities of both receptors for soluble TNF are similar, TNFRSF1B is sometimes more abundantly expressed and thought to associate with TNF, thereby increasing its concentration near TNFRSF1A receptors, and making TNF available to activate TNFRSF1A (a ligand-passing mechanism) [].This entry represents the N-terminal domain of TNFR1B. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
The death domain (DD) is a homotypic protein interaction module composed of a bundle of six α-helices. DD is related in sequence and structure to the death effector domain (DED, see ) and the caspase recruitment domain (CARD, see ), which work in similar pathways and show similar interaction properties []. DD bind each other forming oligomers. Mammals have numerous and diverse DD-containing proteins []. Within these proteins, the DD domains can be found in combination with other domains, including: CARDs, DEDs, ankyrin repeats (), caspase-like folds, kinase domains, leucine zippers, leucine-rich repeats (LRR) (), TIR domains (), and ZU5 domains () [].Some DD-containing proteins are involved in the regulation of apoptosis and inflammation through their activation of caspases and NF-kappaB, which typically involves interactions with TNF (tumour necrosis factor) cytokine receptors [, ]. In humans, eight of the over 30 known TNF receptors contain DD in their cytoplasmic tails; several of these TNF receptors use caspase activation as a signalling mechanism. The DD mediates self-association of these receptors, thus giving the signal to downstream events that lead to apoptosis. Other DD-containing proteins, such as ankyrin, MyD88 and pelle, are probably not directly involved in cell death signalling. DD-containing proteins also have links to innate immunity, communicating with Toll family receptors through bipartite adapter proteins such as MyD88 [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptors 11A and 11B mediate the effects of receptor activator for NF-kappa-B ligand (RANKL), an essential osteoclast regulatory factor. The receptors have opposing effects -activation of TNF receptor 11A by RANKL promotes osteoclast differentiation [], while TNF receptor 11B acts as a soluble decoy receptor for the ligand, thus inhibiting differentiation [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain - a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 10 is activated by TNF-related apoptosis-inducing ligand (TRAIL). Four subtypes of the receptor have been identified: TNF receptors 10A and 10B (also known as death receptor 4 and 5, respectively), which contain a death domain within their C-terminal regions, and TNF receptors 10C and 10D, in which the death domain is not present or is truncated. It has been suggested that the function of the latter two receptors may be to inhibit TRAIL cytotoxicity by competing with the other TRAIL receptors for binding of the ligand [, ].
Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities [, , ]. Tumor necrosis factor (TNF) (also known as TNF-alpha or cachectin) is a monocyte-derived cytotoxin that has been implicated in tumour regression, septic shock and cachexia [, ]. The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine []. A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers []. Both the mature protein and a partially-processed form of the hormone are secreted after cleavage of the propeptide [].There are a number of different families of TNF, but all these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors. The structure of human TNF has been determined to 2.9 A using X-ray crystallography. The protein is trimeric, each subunit consisting of an anti-parallel β-sandwich. The subunits trimerise via a novel edge-to-face packing ofβ-sheets []. It is believed that each TNF molecule has three receptor-interaction sites (between the three subunits), thus allowingsignal transmission by receptor clustering []. This entry represents TNF-alpha, which is a soluble cytokine with a wide variety of functions: it causesdamage to tumour cells but has no effect on normal cells; it is involved in the induction of cachexia; it is a potent pyrogen, causing fever by directaction or by stimulation of interleukin-1 secretion; and it can stimulatecell proliferation and induce cell differentiation under certain conditions.
Viral TNFR homologues include vaccinia virus (VACV) cytokine response modifier E (CrmE) [], an encoded TNFR that shares significant sequence similarity with mammalian type 2 TNF receptors (TNFSFR1B, p75, TNFR type 2) [], a cowpox virus encoded cytokine-response modifier B (CrmB) [], which is a secreted form of TNF receptor that can contribute to the modification of TNF-mediated antiviral processes, and a myxoma virus (MYXV) T2 (M-T2) protein that binds and inhibits rabbit TNF-alpha []. The CrmE structure confirms that the canonical TNFR fold is adopted, but only one of the two "ligand-binding"loops of TNFRSF1A is conserved, suggesting a mechanism for the higher affinity of poxvirusTNFRs for TNFalpha over lymphotoxin-alpha []. CrmB protein specifically binds TNF-alpha and TNF-beta indicating that cowpox virus seeks to invade antiviral processes mediated by TNF. Intracellular M-T2 blocks virus-induced lymphocyte apoptosis via a highly conserved viral preligand assembly domain (vPLAD), which controls receptor signaling competency prior to ligand binding [].This entry represents the N-terminal domain of viral TNFRs. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 13B (also known as transmembrane activator and CAML interactor (TACI)) functions as a receptor for B-cell activating factor (BAFF) []. Mutations in TNF receptor 13B cause common variable immunodeficiency (CVID) and IgA deficiency [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain- a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 1B (also known as TNF-R2 and CD120b antigen) is present on many cell types, especially those of myeloid origin, and is strongly expressed on stimulated T and B lymphocytes. It is the main TNF receptor found on circulating T cells and is the major mediator of autoregulatory apoptosis in CD8+ cells [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain - a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signaling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 1A (also known as TNF-R1 and CD120a antigen) contains a death domain within its C-terminal region that mediates interactions with several proteins involved in signaling the downstream effects of TNF. Activation of the receptor may induce either cell survival or apoptosis, the latter proceeding via recruitment of the adaptor protein FADD and caspase-8 to the receptor complex []. Defects in TNF receptor 1A are the cause of familial hibernian fever (FHF) - an autosomal dominant disease characterised by recurrent fever, abdominal pain, localised tender skin lesions and myalgia.
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain - a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. This entry represents tumour necrosis factor receptor superfamily member 3 (TNF receptor 3; also known as lymphotoxin-beta receptor). TNF receptor 3 acts as a receptor for the heterotrimer of lymphotoxin-alpha and beta, and also for the TNF ligand LIGHT. Activation of the receptor promotes apoptosis via recruitment of TNFR-associated factor 3 (TRAF3) [].
TIMP-3 (MEROPS identifier I35.003) is known to inhibit matrix metalloproteinases, aggrecanases, and tumour necrosis factor (TNF)-alpha-converting enzyme (TACE, ADAM17), and mutations in the Human TIMP-3 gene cause a dominantly inherited, adult-onset blindness (Sorsby's fundus dystrophy or SFD) []. Deletion of the Mouse Timp3 gene results in an increase in TNF-alpha converting enzyme activity, constitutive release of TNF and activation of TNF signalling in the liver []. The knockout animals also develop spontaneous air space enlargement in the lung that is evident at 2 weeks after birth and progresses with age of the animal, and succumb to death as early as 13 months of age []. TIMP-3 has been shown to regulate agonist-induced vascular remodelling and hypertension [].Tissue inhibitors of metalloproteinases (TIMPs) are natural inhibitors of matrix metalloproteinases (MMPs) found in most tissues and body fluids. By inhibiting MMPs activities, they participate in tissue remodeling of the extracellular matrix (ECM). The balance between MMPs and TIMPs activities is involved in both normal and pathological events such as wound healing, tissue remodeling, angiogenesis, invasion, tumourigenesis and metastasis []. TIMPs also exhibit functions that appear to be independent of their metalloproteinase inhibitory capacity []. There are four mammalian TIMPs (TIMP-1 to -4), and each TIMP has its own profile of metalloproteinase inhibition.
Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities [, , ]. Tumor necrosis factor (TNF) (also known as TNF-alpha or cachectin) is a monocyte-derived cytotoxin that has been implicated in tumour regression, septic shock and cachexia [, ]. The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine []. A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers []. Both the mature protein and a partially-processed form of the hormone are secreted after cleavage of the propeptide [].There are a number of different families of TNF, but all these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors. TNF exerts its function mainly through two TNF receptors, TNF-1 and TNF-2, which are expressed on nearly all cells of the body. This entry represents TNF-2.TNFs and their receptors can select and kill virus-infected cells [].Poxviruses are large DNA viruses that encode many proteins capable of interfering with host immune functions, including soluble versions of cytokine receptors such as vTNFalpha-2 (viral TNFalpha receptor 2). These soluble cytokine receptors effectively block cytokine activity and modulate viral virulence. The C22L type receptor in vaccinia virus is equivalent to the CrmB (cytokine response modifier B) protein in cowpox virus [, , ].
TAB2 (TGF-beta-activated kinase 1 and MAP3K7-binding protein 2) is an adaptor protein that regulates activation of TAK1, a MAP kinase kinase kinase (MAPKKK), through linking TAK1 to TRAF6 in the Interleukin-1 (IL-1) induced NF-kappaB activation pathway []. TAB3 is a TAB2-like TAK1-binding protein that activates NF-kappaB similar to TAB2 []. It activates TAK1 and regulates its association with TRAF2 and TRAF6. Moreover, TAB3 interacts with TRAF6 and TRAF2 in an IL-1- and a TNF-dependent manner, respectively. TAB2 and TAB3 function redundantly as mediators of TAK1 activation in IL-1 and TNF signal transduction []. Both of them contain an N-terminal CUE domain, a coiled-coil (CC) region, a TAK1-binding domain and a C-terminal Npl4 zinc finger (NZF) ubiquitin-binding domain (UBD) [].This entry represents the CUE domain found in TAB2 and TAB3.
Interleukin-10 (IL-10) is a protein that inhibits the synthesis of a number of cytokines, including IFN-gamma, IL-2, IL-3, TNF and GM-CSF produced by activated macrophages and by helper T cells. Structurally, IL-10 is a protein of about 160 amino acids that contains four conserved cysteines involved in disulphide bonds []. IL-10 is highly similar to the Epstein-Barr virus (strain GD1) (HHV-4) (Human herpesvirus 4) BCRF1 protein which inhibits the synthesis of gamma-interferon and to Equid herpesvirus 2 (Equine herpesvirus 2) protein E7.It is also similar, but to a lesser degree, with human protein mda-7 [], a protein which has antiproliferative properties in human melanoma cells. Mda-7 only contains two of the four cysteines of IL-10.This entry represents the interleukin-10, interleukin-19, interleukin-20, interleukin-22, interleukin-24 and interleukin-26 family.
Neurotrophins are a family of secreted proteins that regulate development, maintenance and function of vertebrate nervous systems. They act via two different classes of receptor: p75NTR (a member of the TNF receptor superfamily), and neurotrophic tyrosine kinase receptors (NTRKs) - also known as tropomyosin-related kinases (Trks) []. NTRKs are multi-domain, transmembrane proteins - in addition to their cytoplasmic kinase domains, members of the family possess a number of extracellular leucine-rich repeat (LRR) and Ig-like C2-type regions. Ligand binding induces them to dimerise, resulting in activation of their cytoplasmic tyrosine kinase domains. The activated receptors couple to a variety of intracellular signalling cascades, including the Ras, phosphatidylinositol-3-kinase (PI-3 kinase), mitogen-activated protein (MAP) kinase, and phospholipase C (PLC)-gamma pathways [].
Adenoviruses are medium-sized, non-enveloped viruses containing double-stranded DNA. They can cause a variety of diseases including pneumonia, cystitis, conjunctivitis and diarrhoea, all of which can be fatal to patients who are immunocompromised []. These viruses have many mechanisms to evade the host immune response, including several proteins which are expressed as part of the early transcription unit 3 (E3) []. One of the regions of E3, known as the E3B region, encodes three proteins known as 10.4K, 14.5K and 14.7K. Two of these proteins, 10.4K and 14.5K, formthe RID complex (receptor internalisation and degradation) which protects the infected cell from host-induced lysis by clearing the the TNF and Fas receptors from the cell surface []. Other receptors, such as the epidermal growth factor receptor, are also known to be cleared by RID []. This entry represents the E3B region 10.4K protein, also known as the RID alpha subunit.
This is a PUB domain (PNGase/UBA- or UBX-containing domain), found in E3 ubiquitin-protein ligase RNF31, also known as Ring finger protein 31 and HOIL-1-interacting protein (HOIP) []. RNF31/HOIP has been shown to contribute to inborn human immunity disorders, in which RNF31/HOIP missense mutation at PUB domain gives rise to the de-stabilized LUBAC complex (linear ubiquitin chain assembly complex) and subsequently causes the auto-inflammation and immunodeficiency. In addition, RNF31 is reported to modify ERK and JNK pathways leading to cisplatin resistance []. Functional studies indicate that HOIP and OTULIN interact and act as a bimolecular editing pair for linear ubiquitin signals where the HOIP-PUB domain binds to the PUB interacting motif (PIM) of OTULIN and the chaperone VCP/p9. This interaction plays an important role where the HOIP binding to OTULIN is required for the recruitment of OTULIN to the TNF receptor complex and to counteract HOIP-dependent activation of the NF-KB pathway [, ].
Although apparently functionally unrelated, intracellular TRAFs and extracellular meprins share a conserved region of about 180 residues, the meprin and TRAF homology (MATH) domain []. Meprins are mammalian tissue-specific metalloendopeptidases of the astacin family implicated in developmental, normal and pathological processes by hydrolysing a variety of proteins. Various growth factors, cytokines, and extracellular matrix proteins are substrates for meprins. They are composed of five structural domains: an N-terminal endopeptidase domain, a MAM domain (see ), a MATH domain, an EGF-like domain (see ) and a C-terminal transmembrane region. Meprin A and B form membrane bound homotetramer whereas homooligomers of meprin A are secreted. A proteolitic site adjacent to the MATH domain, only present in meprin A, allows the release of the protein from the membrane [].TRAF proteins were first isolated by their ability to interact with TNF receptors []. They promote cell survival by the activation of downstream protein kinases and, finally, transcription factors of the NF-kB and AP-1 family. The TRAF proteins are composed of 3 structural domains: a RING finger (see ) in the N-terminal part of the protein, one to seven TRAF zinc fingers (see ) in the middle and the MATH domain in the C-terminal part []. The MATH domain is necessary and sufficient for self-association and receptor interaction. From the structural analysis two consensus sequence recognised by the TRAF domain have been defined: a major one, [PSAT]x[QE]E and a minor one, PxQxxD [].The structure of the TRAF2 protein reveals a trimeric self-association of the MATH domain []. The domain forms a new, light-stranded antiparallel β-sandwich structure. A coiled-coil region adjacent to the MATH domain is also important for the trimerisation. The oligomerisation is essential for establishing appropriate connections to form signalling complexes with TNF receptor-1. The ligand binding surface of TRAF proteins is located in β-strands 6 and 7 [].
This group of sequences represent the p10 subunit found in caspases. Caspases (Cysteine-dependent ASPartyl-specific proteASE) are cysteine peptidases that belong to the MEROPS peptidase family C14 (caspase family, clan CD) based on the architecture of their catalytic dyad or triad []. Caspases are tightly regulated proteins that require zymogen activation to become active, and once active can be regulated by caspase inhibitors. Activated caspases act as cysteine proteases, using the sulphydryl group of a cysteine side chain for catalysing peptide bond cleavage at aspartyl residues in their substrates. The catalytic cysteine and histidine residues are on the p20 subunit after cleavage of the p45 precursor.Caspases are mainly involved in mediating cell death (apoptosis) [, , ]. They have two main roles within the apoptosis cascade: as initiators that trigger the cell death process, and as effectors of the process itself. Caspase-mediated apoptosis follows two main pathways, one extrinsic and the other intrinsic or mitochondrial-mediated. The extrinsic pathway involves the stimulation of various TNF (tumour necrosis factor) cell surface receptors on cells targeted to die by various TNF cytokines that are produced by cells such as cytotoxic T cells. The activated receptor transmits the signal to the cytoplasm by recruiting FADD, which forms a death-inducing signalling complex (DISC) with caspase-8. The subsequent activation of caspase-8 initiates the apoptosis cascade involving caspases 3, 4, 6, 7, 9 and 10. The intrinsic pathway arises from signals that originate within the cell as a consequence of cellular stress or DNA damage. The stimulation or inhibition of different Bcl-2 family receptors results in the leakage of cytochrome c from the mitochondria, and the formation of an apoptosome composed of cytochrome c, Apaf1 and caspase-9. The subsequent activation of caspase-9 initiates the apoptosis cascade involving caspases 3 and 7, among others. At the end of the cascade, caspases act on a variety of signal transduction proteins, cytoskeletal and nuclear proteins, chromatin-modifying proteins, DNA repair proteins and endonucleases that destroy the cell by disintegrating its contents, including its DNA. The different caspases have different domain architectures depending upon where they fit into the apoptosis cascades, however they all carry the catalytic p10 and p20 subunits.Caspases can have roles other than in apoptosis, such as caspase-1 (interleukin-1 beta convertase) (), which is involved in the inflammatory process. The activation of apoptosis can sometimes lead to caspase-1 activation, providing a link between apoptosis and inflammation, such as during the targeting of infected cells. Caspases may also be involved in cell differentiation [].
This entry represents the C-terminal conserved domain found in caspases mostly from animals. This domain includes the core of p45 (45kDa) precursor of caspases, which can be processed to produce the active p20 (20kDa) and p10 (10kDa) subunits. Caspases (Cysteine-dependent ASPartyl-specific proteASE) are cysteine peptidases that belong to the MEROPS peptidase family C14 (caspase family, clan CD) based on the architecture of their catalytic dyad or triad []. Caspases from animals can be classified as C14A subfamiy. Caspases are tightly regulated proteins that require zymogen activation to become active, and once active can be regulated by caspase inhibitors. Activated caspases act as cysteine proteases, using the sulphydryl group of a cysteine side chain for catalysing peptide bond cleavage at aspartyl residues in their substrates. The catalytic cysteine and histidine residues are on the p20 subunit after cleavage of the p45 precursor.Caspases are mainly involved in mediating cell death (apoptosis) [, , ]. They have two main roles within the apoptosis cascade: as initiators that trigger the cell death process, and as effectors of the process itself. Caspase-mediated apoptosis follows two main pathways, one extrinsic and the other intrinsic or mitochondrial-mediated. The extrinsic pathway involves the stimulation of various TNF (tumour necrosis factor) cell surface receptors on cells targeted to die by various TNF cytokines that are produced by cells such as cytotoxic T cells. The activated receptor transmits the signal to the cytoplasm by recruiting FADD, which forms a death-inducing signalling complex (DISC) with caspase-8. The subsequent activation of caspase-8 initiates the apoptosis cascade involving caspases 3, 4, 6, 7, 9 and 10. The intrinsic pathway arises from signals that originate within the cell as a consequence of cellular stress or DNA damage. The stimulation or inhibition of different Bcl-2 family receptors results in the leakage of cytochrome c from the mitochondria, and the formation of an apoptosome composed of cytochrome c, Apaf1 and caspase-9. The subsequent activation of caspase-9 initiates the apoptosis cascade involving caspases 3 and 7, among others. At the end of the cascade, caspases act on a variety of signal transduction proteins, cytoskeletal and nuclear proteins, chromatin-modifying proteins, DNA repair proteins and endonucleases that destroy the cell by disintegrating its contents, including its DNA. The different caspases have different domain architectures depending upon where they fit into the apoptosis cascades, however they all carry the catalytic p10 and p20 subunits.Caspases can have roles other than in apoptosis, such as caspase-1 (interleukin-1 beta convertase) (), which is involved in the inflammatory process. The activation of apoptosis can sometimes lead to caspase-1 activation, providing a link between apoptosis and inflammation, such as during the targeting of infected cells. Caspases may also be involved in cell differentiation [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises morethan 20 type-I transmembrane proteins. Family members are defined based onsimilarity in their extracellular domain - a region that contains manycysteine residues arranged in a specific repetitive pattern []. Thecysteines allow formation of an extended rod-like structure, responsible forligand binding [].Upon receptor activation, different intracellular signalling complexes areassembled for different members of the TNFR superfamily, depending on theirintracellular domains and sequences []. Activation of TNFRs can thereforeinduce a range of disparate effects, including cell proliferation,differentiation, survival, or apoptotic cell death, depending upon thereceptor involved [].TNFRs are widely distributed and play important roles in many crucialbiological processes, such as lymphoid and neuronal development, innate andadaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention andtreatment of many diseases, such as viral infections, coronary heartdisease, transplant rejection, and immune disease [].This entry includes the TNF receptors 13C and 17. TNFR 17 acts as a receptor for both a proliferation-inducing ligand (APRIL) and B cell-activating factor (BAFF, also called BLyS or TALL-I) [, ]. It is preferentially expressed by mature B-cells, suggesting a that it is involved in cell survival and proliferation. It has been demonstrated that it acts through the activation of NF-kappa-B and JNK pathways []. TNFR 13C is a B-cell receptor specific for BAFF and it promotes the mature B-cells survival and response [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 13C is also known as B-cell activating factor (BAFF) receptor []. It appears to be the principal receptor in mediating BAFF-dependent B-cell signalling, and plays a critical role in late-stage B-cell maturation and survival [].
Apoptosis signal-regulating kinases (ASK1/2/3 or MAP3K5/6/15) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that mediate cellular responses to redox stress and inflammatory cytokines and play a key role in innate immunity and viral infection. This kind of signalling kinases are regulated by oligomerization and regulatory domains. In its N-terminal there is a thioredoxin-binding domain that negatively regulates activity and a TNF receptor-associated factors (TRAFs)-binding domain which triggers ASK activation and kinase activity. TRAFs-binding domain is composed by 14 helices, which form seven tetratricopeptide repeats (TPRs), followed by a PH-like domain to complete de central regulatory domain of ASK. The central regulatory region promotes ASK1 activity via its PH domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. The PH-like domain, adjacent to the kinase domain, is required together with an intact TPR region for ASK1 activity.The major role of the central regulatory region is to bring the thioredoxin-binding domain into close proximity to the kinase domain to inhibit its activity [].This PH-like domain is found in the regulatory region of ASK1/2/3 (also known as MAP3K5/6/15). The central regulatory region of ASK1 mediates a compact arrangement of the kinase and thioredoxin-binding domains which allows the binding of substrates for phosphorylation. This PH-like domain adopts the typical form of two antiparallel β-sheets followed by a C-terminal amphipathic helix [].
Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities [, , ]. Tumor necrosis factor (TNF) (also known as TNF-alpha or cachectin) is a monocyte-derived cytotoxin that has been implicated in tumour regression, septic shock and cachexia [, ]. The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine []. A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers []. Both the mature protein and a partially-processed form of the hormone are secreted after cleavage of the propeptide [].There are a number of different families of TNF, but all these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors. Lymphotoxin-alpha (LT-alpha or TNF-beta) and lymphotoxin-beta (LT-beta) arerelated cytokines produced by lymphocytes. The proteins are cytotoxic for awide range of tumour cells in vitroand in vivo.This entry represents Tumour necrosis factor C (TNFC or LT-beta). The gene isfound next to the TNF-LT locus in the major histocompatibility complex (MHC),a region of the MHC with possible linkage to autoimmune disease []. It is possible that a surface LT-alpha/LT-beta complex may have a specific role in immune regulation distinct from the functions ascribed to TNF [].
RIP kinases serve as essential sensors of cellular stress. Vertebrates contain several types containing a homologous N-terminal kinase domain and varying C-terminal domains [, ]. RIP1 harbours a C-terminal Death domain (DD), which binds death receptors (DRs) including TNF receptor 1, Fas, TNF-related apoptosis-inducing ligand receptor 1 (TRAILR1), and TRAILR2. It also interacts with other DD-containing adaptor proteins such as TRADD and FADD. RIP1 plays a crucial role in determining a cell's fate, between survival or death, following exposure to stress signals. It is important in the signaling of NF-kappaB and MAPKs, and it links DR-associated signaling to reactive oxygen species (ROS) production. Abnormal RIP1 function may result in ROS accumulation affecting inflammatory responses, innate immunity, stress responses, and cell survival [, ]. DDs (Death domains) are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes [, ].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 18 is also known as glucocorticoid-induced TNFR family-related gene (GITR) and activation-inducible TNFR family member (AITR). Expression of the receptor by T-lymphocytes has been shown to have an anti-apoptotic effect, indicating that it may play a role in the regulation of T-cell receptor-mediated cell death [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain - a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 19, also known as toxicity and JNK inducer (TAJ) and TROY, is highly expressed during embryonic development, where it may act as a regulator of cell activation and cell death []. In adult tissues, the receptor is expressed in the central nervous system, and may mediate the inhibitory effectsof myelin upon axon regeneration [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 21, also termed death receptor 6 (DR6), is expressed ubiquitously, with high expression in lymphoid organs, heart, brain and pancreas. The receptor plays an important regulatory role in the generation of adaptive immunity and may be involved in tumour cell survival and immune evasion []. It has also been implicated in the pathogenesis of Alzheimer's disease, as activation of the receptor by beta-amyloid precursor protein triggers neuronal death via a caspase-dependent pathway [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains andsequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 14 is also known as herpesvirus entry mediator (HVEM). It plays an important role in the entry of herpes simplex virus into cells, and hence pathogenesis of the virus [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 19-like, also known as receptor expressed in lymphoid tissues (RELT), is abundantly expressed in hematologic tissues such as spleen, lymph node, and peripheral blood leukocytes, as well as in leukemias and lymphomas []. The receptor may play a role in the regulation of immune responses [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 16 (also known as nerve growth factor receptor (NGFR) and p75NTR)) acts as a low affinity receptor for neurotrophins. The receptor mediates a variety of contradictory cellular functions, including cell survival or apoptosis, promotion or inhibition of axonal growth, and facilitation or attenuation of proliferation, depending on the cellular context []. The receptor may also play a role in inflammation, and has been implicated in the pathogenesis of asthma []. A single partial match was also found, , a translated human cDNA sequence that fails to match motifs 1 and 2.
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain- a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 25 (alternatively known as death receptor 3 (DR3) and lymphocyte-associated receptor of death (LARD) is expressed primarily on the surface of thymocytes and lymphocytes []. The receptor contains a death domain in its C-terminal region, and acts as a key regulator of life/death decisions during thymocyte development [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 7, otherwise known as CD27 antigen, is expressed on discrete subpopulations of T-and B-cells []. The receptor plays a vital role in the generation and long-term maintenance of T-cell immunity [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain - a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 8 (also known as CD30 and Ki-1 antigen) was originally described as a marker of Hodgkin's and Reed-Sternberg cells in Hodgkin's lymphoma. Expression of the receptor is largely restricted to virus-infected lymphocytes, neoplasms of lymphoid origin and a subset of activated T cells that produce Th2-type cytokines []. The receptor has pleiotropic biological functions, including inducement apoptosis and enhancement of cell survival [].
Apoptosis signal-regulating kinases (ASK1/2/3 or MAP3K5/6/15) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that mediate cellular responses to redox stress and inflammatory cytokines and play a key role in innate immunity and viral infection. This kind of signalling kinases are regulated by oligomerization and regulatory domains. In its N-terminal there is a thioredoxin-binding domain that negatively regulates activity and a TNF receptor-associated factors (TRAFs)-binding domain which triggers ASK activation and kinase activity. TRAFs-binding domain is composed by 14 helices, which form seven tetratricopeptide repeats (TPRs), followed by a PH-like domain to complete de central regulatory domain of ASK. The central regulatory region promotes ASK1 activity via its PH domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. The PH-like domain, adjacent to the kinase domain, is required together with an intact TPR region for ASK1 activity.The major role of the central regulatory region is to bring the thioredoxin-binding domain into close proximity to the kinase domain to inhibit its activity [].
Apoptosis signal-regulating kinases (ASK1/2/3 or MAP3K5/6/15) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that mediate cellular responses to redox stress and inflammatory cytokines and play a key role in innate immunity and viral infection. This kind of signalling kinases are regulated by oligomerization and regulatory domains. In its N-terminal there is a thioredoxin-binding domain that negatively regulates activity and a TNF receptor-associated factors (TRAFs)-binding domain which triggers ASK activation and kinase activity. TRAFs-binding domain is composed by 14 helices, which form seven tetratricopeptide repeats (TPRs), followed by a PH-like domain to complete de central regulatory domain of ASK. The central regulatory region promotes ASK1 activity via its PH domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. The PH-like domain, adjacent to the kinase domain, is required together with an intact TPR region for ASK1 activity.The major role of the central regulatory region is to bring the thioredoxin-binding domain into close proximity to the kinase domain to inhibit its activity [].This domain represents a predicted non-heme-binding version of the globin domain identified in ASK1/2/3. It displays strongest affinities to the HisK-N family of sensor domains, which inhibit histidine kinase activation required for sporulation in bacteria of the firmicutes lineage. This globin domain is predicted to represent an independent sensory element recognizing a fatty acid or a related membrane-derived molecule which regulates activity of the ASK signalosome in apoptosis [].
Apoptosis signal-regulating kinases (ASK1/2/3 or MAP3K5/6/15) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that mediate cellular responses to redox stress and inflammatory cytokines and play a key role in innate immunity and viral infection. This kind of signalling kinases are regulated by oligomerization and regulatory domains. In its N-terminal there is a thioredoxin-binding domain that negatively regulates activity and a TNF receptor-associated factors (TRAFs)-binding domain which triggers ASK activation and kinase activity. TRAFs-binding domain is composed by 14 helices, which form seven tetratricopeptide repeats (TPRs), followed by a PH-like domain to complete de central regulatory domain of ASK. The central regulatory region promotes ASK1 activity via its PH domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. The PH-like domain, adjacent to the kinase domain, is required together with an intact TPR region for ASK1 activity.The major role of the central regulatory region is to bring the thioredoxin-binding domain into close proximity to the kinase domain to inhibit its activity [].This is an uncharacterised DRHyd domain observed in MAP3K5/6/15. It potentially generates nucleotide-derived signal recognised by the TPR-S domain found in the same proteins [].
Neurotrophins are a family of secreted proteins that regulate development, maintenance and function of vertebrate nervous systems. They act via two different classes of receptor: p75NTR (a member of the TNF receptor superfamily), and neurotrophic tyrosine kinase receptors (NTRKs) - also known as tropomyosin-related kinases (Trks) []. NTRKs are multi-domain, transmembrane proteins - in addition to their cytoplasmic kinase domains, members of the family possess a number of extracellular leucine-rich repeat (LRR) and Ig-like C2-type regions. Ligand binding induces them to dimerise, resulting in activation of their cytoplasmic tyrosine kinase domains. The activated receptors couple to a variety of intracellular signalling cascades, including the Ras, phosphatidylinositol-3-kinase (PI-3 kinase), mitogen-activated protein (MAP) kinase, and phospholipase C (PLC)-gamma pathways []. This entry represents NTRK2 (also termed TrkB) is a high-affinity receptor for brain-derived neurotrophic factor (BDNF) and neurotrophin (NT-4). It is broadly expressed in the nervous system, and is also found in some non neural tissues []. The receptor is involved in synaptogenesis and neuronal development []. It plays a crucial role in learning and memory [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type I transmembrane proteins. Family members are defined based on similarity in their extracellular domain, a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rodlike structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. This entry represents TNF receptor 4 (also known as OX40 and CD134 antigen) is expressed primarily on activated CD4(+) T cells. Activation of the receptor increases the proinflammatory activity of these cells and enhances their long-term survival [].
Neurotrophins are a family of secreted proteins that regulate development, maintenance and function of vertebrate nervous systems. They act via two different classes of receptor: p75NTR (a member of the TNF receptor superfamily), and neurotrophic tyrosine kinase receptors (NTRKs) - also known as tropomyosin-related kinases (Trks) []. NTRKs are multi-domain, transmembrane proteins - in addition to their cytoplasmic kinase domains, members of the family possess a number of extracellular leucine-rich repeat (LRR) and Ig-like C2-type regions. Ligand binding induces them to dimerise, resulting in activation of their cytoplasmic tyrosine kinase domains. The activated receptors couple to a variety of intracellular signalling cascades, including the Ras, phosphatidylinositol-3-kinase (PI-3 kinase), mitogen-activated protein (MAP) kinase, and phospholipase C (PLC)-gamma pathways []. NTRK3 (also termed TrkC) is a high-affinity receptor for neurotrophin-3 (NT-3). The receptor is widely expressed in the developing nervous system, and is also found in many non-neuronal tissues []. In addition to roles in peripheral nerve cell myelination, mediating the inhibitory effects of NT-3 on this process [].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain - a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 5 (also known as CD40 antigen) is expressed by a wide variety of cell types, including B lymphocytes, macrophages, dendritic cells, endothelial cells and epithelial cells. The receptor plays an important role in T cell-mediated B lymphocyte activation [].
Neurotrophins are a family of secreted proteins that regulate development, maintenance and function of vertebrate nervous systems. They act via two different classes of receptor: p75NTR (a member of the TNF receptor superfamily), and neurotrophic tyrosine kinase receptors (NTRKs) - also known as tropomyosin-related kinases (Trks) []. NTRKs are multi-domain, transmembrane proteins - in addition to their cytoplasmic kinase domains, members of the family possess a number of extracellular leucine-rich repeat (LRR) and Ig-like C2-type regions. Ligand binding induces them to dimerise, resulting in activation of their cytoplasmic tyrosine kinase domains. The activated receptors couple to a variety of intracellular signalling cascades, including the Ras, phosphatidylinositol-3-kinase (PI-3 kinase), mitogen-activated protein (MAP) kinase, and phospholipase C (PLC)-gamma pathways []. NTRK1 (also termed TrkA) is a high-affinity receptor for nerve growth factor (NGF). The receptor is expressed in the dorsal root ganglia, trigeminal ganglia and sympathetic neurons of the peripheral nervous system, and in basal forebrain cholinergic neurons []. It is also expressed in peripheral sites, such as scalp skin []. Whereas p75NTR activation by NGF induces apoptosis, NTRK1 mediates the growth factor's cell survival-promoting effects [].
Apoptosis signal-regulating kinases (ASK1/2/3 or MAP3K5/6/15) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that mediate cellular responses to redox stress and inflammatory cytokines and play a key role in innate immunity and viral infection. This kind of signalling kinases are regulated by oligomerization and regulatory domains. In its N-terminal there is a thioredoxin-binding domain that negatively regulates activity and a TNF receptor-associated factors (TRAFs)-binding domain which triggers ASK activation and kinase activity. TRAFs-binding domain is composed by 14 helices, which form seven tetratricopeptide repeats (TPRs), followed by a PH-like domain to complete de central regulatory domain of ASK. The central regulatory region promotes ASK1 activity via its PH domain but also facilitates ASK1 autoinhibition by bringing the thioredoxin-binding and kinase domains into close proximity. The PH-like domain, adjacent to the kinase domain, is required together with an intact TPR region for ASK1 activity.The major role of the central regulatory region is to bring the thioredoxin-binding domain into close proximity to the kinase domain to inhibit its activity [].This domain corresponds to the TRAFs-binding domain found at the N terminus of some MAP3Ks. This domain includes seven tetratricopeptide repeats (TPRs) and, together with th PH-like domain, constitutes the central regulatory domain of ASK1.
A number of proteins, some of which are known to be receptors for growth factors, have been found to contain a cysteine-rich domain of about 110 to 160 amino acids in their N-terminal part, that can be subdivided into four (or in some cases, three) modules of about 40 residues containing 6 conserved cysteines. Some of the proteins containing this domain are listed below [, , ]:Tumor Necrosis Factor type I and type II receptors (TNFR). Both receptors bind TNF-alpha and TNF-beta, but are only similar in the cysteine-rich region. TNFR contains four cysteine-rich domain modules (CRDs), termed CRD1 through CRD4. CRD2 and CRD3 are known as TNF-binding domains [].Shope fibroma virus soluble TNF receptor (protein T2)Lymphotoxin alpha/beta receptorLow-affinity nerve growth factor receptor (LA-NGFR) (p75)CD40 (Bp50), the receptor for the CD40L (or TRAP) cytokineCD27, the receptor for the CD27L cytokineCD30, the receptor for the CD30L cytokineT-cell protein 4-1BB, the receptor for the 4-1BBL putative cytokine FAS antigen (or APO-1), the receptor for FASL, a protein involved in apoptosis (programmed cell death)T-cell antigen OX40, the receptor for the OX40L cytokineWsl-1, a receptor (for a yet undefined ligand) that mediates apoptosisVaccinia virus protein A53 (SalF19R)It has been shown []that the six cysteines all involved in intrachaindisulphide bonds. A schematic representation of the structure of the 40 residuemodule of these receptors is shown below:+-------------+ +--------------+| | | |xCxxxxxxxxxxxxxCxCxxCxxxxxxxxxCxxxxCxx| |+------------+'C': conserved cysteine involved in a disulphide bond.
Like all apoptotic cell death, T cell receptor (TCR)-mediated death can bedivided into two phases: an inductive phase and an effector phase. The effector phase includes a sequence of steps that are common to apoptosis inmany cell types, which, if not interrupted, will lead to cell death. Theinduction phase, which often requires the expression of new genes, consistsof a set of signals that activate the effector phase. Outside the thymus,most, if not all, of the TCR-mediated apoptosis of mature T cells (sometimesreferred to as activation-induced cell death (AICD)) is induced through thesurface antigen Fas pathway: activation through the TCR induces expressionof the Fas (CD95) ligand (FasL); the expression of FasL on either aneighbouring cell, or on the Fas-bearing cell, induces trimerisation of Fas,which then initiates a signal-transduction cascade, leading to apoptosis of the Fas-bearing cell. This commitment stage requires the activation of keydeath-inducing enzymes, termed caspases, which act by cleaving proteins thatare essential for cell survival and proliferation[, ]. However whathappens to FasL itself remains unknown. It is possible that it is cleavedfrom the effector cells and internalised into the target cells; it may bedownregulated in the effector cells; or it may be phagocytosed by the targetcells.Fas is also known to be essential in the death of hyperactivated peripheralCD4 cells: in the absence of Fas, mature peripheral T cells do not die, butthe activated cells continue to proliferate, producing cytokines that leadto grossly enlarged lymph nodes and spleen. Defects in the Fas-FasL systemare associated with various disease syndromes. Mice with non-functional Fasor FasL display characteristics of lymphoproliferative disorder, such as lymphadenopathy, splenomegaly, and elevated secretion of IgM and IgG. Thesemice also secrete anti-DNA autoantibodies and rheumatoid factor [].FasL (also known as tumor necrosis factor ligand superfamily member 6) is a 40kDa type II membrane protein belonging to the tumour necrosisfactor (TNF) family. Its binding to the cognate Fas receptor triggers the apoptosis that plays a pivotal role in the maintenance of immune system homeostasis. It is expressed on activated lymphocytes, NK cells,platelets, certain immune-privileged cells and some tumour cells[, ]. The cell death-inducing property of FasL has been associated with its extracellular domain, which can be cleaved off by metalloprotease activity to produce soluble FasL [].Human and mouse FasL induce apoptosis in cells expressing either mouse orhuman Fas with the same specificity. Although the amino acid sequence ofFasL is highly conserved between human and mouse, the similarity betweenhuman and murine Fas is much less pronounced. Greater conservation of theligand than the receptor is also observed in other members of the TNF family.By comparison with other TNF family members, FasL has a long N-terminal intracellular region rich in proline residues, which is known tobind to the SH3 domain. SH3 domains play important roles in mediating specificprotein-protein interactions, specifically in the cytoskeleton.
This group of sequences represent the p45 (45kDa) precursor of caspases, which can be processed to produce the active p20 (20kDa) and p10 (10kDa) subunits. Caspases (Cysteine-dependent ASPartyl-specific proteASE) are cysteine peptidases that belong to the MEROPS peptidase family C14 (caspase family, clan CD) based on the architecture of their catalytic dyad or triad []. Caspases are tightly regulated proteins that require zymogen activation to become active, and once active can be regulated by caspase inhibitors. Activated caspases act as cysteine proteases, using the sulphydryl group of a cysteine side chain for catalysing peptide bond cleavage at aspartyl residues in their substrates. The catalytic cysteine and histidine residues are on the p20 subunit after cleavage of the p45 precursor.Caspases are mainly involved in mediating cell death (apoptosis) [, , ]. They have two main roles within the apoptosis cascade: as initiators that trigger the cell death process, and as effectors of the process itself. Caspase-mediated apoptosis follows two main pathways, one extrinsic and the other intrinsic or mitochondrial-mediated. The extrinsic pathway involves the stimulation of various TNF (tumour necrosis factor) cell surface receptors on cells targeted to die by various TNF cytokines that are produced by cells such as cytotoxic T cells. The activated receptor transmits the signal to the cytoplasm by recruiting FADD, which forms a death-inducing signalling complex (DISC) with caspase-8. The subsequent activation of caspase-8 initiates the apoptosis cascade involving caspases 3, 4, 6, 7, 9 and 10. The intrinsic pathway arises from signals that originate within the cell as a consequence of cellular stress or DNA damage. The stimulation or inhibition of different Bcl-2 family receptors results in the leakage of cytochrome c from the mitochondria, and the formation of an apoptosome composed of cytochrome c, Apaf1 and caspase-9. The subsequent activation of caspase-9 initiates the apoptosis cascade involving caspases 3 and 7, among others. At the end of the cascade, caspases act on a variety of signal transduction proteins, cytoskeletal and nuclear proteins, chromatin-modifying proteins, DNA repair proteins and endonucleases that destroy the cell by disintegrating its contents, including its DNA. The different caspases have different domain architectures depending upon where they fit into the apoptosis cascades, however they all carry the catalytic p10 and p20 subunits.Caspases can have roles other than in apoptosis, such as caspase-1 (interleukin-1 beta convertase) (), which is involved in the inflammatory process. The activation of apoptosis can sometimes lead to caspase-1 activation, providing a link between apoptosis and inflammation, such as during the targeting of infected cells. Caspases may also be involved in cell differentiation [].There are non-peptidase homologues in the caspase family, such as CASP8 and FADD-like apoptosis regulator (CASH/c-FLIP), which suppresses death receptor induced apoptosis and TCR activation induced cell death by inhibiting caspase-8 activation [, , ].
Proteins in this family include the envelope glycoprotein and the pre-small/secreted glycoprotein from Filoviridae []. The envelope glycoprotein can be cleaved into 3 chains: GP1, GP2 and GP2-delta.GP1 is responsible for binding to the receptor(s), such as CD209 and CLEC4M, on target cells. These interactions not only facilitate virus cell entry, but also allow capture of viral particles by dendritic cells (DCs) and subsequent transmission to susceptible cells without DCs infection (trans infection) [].GP2 acts as a class I viral fusion protein. It is responsible for penetration of the virus into the cell cytoplasm by mediating the fusion of the membrane of the endocytosed virus particle with the endosomal membrane []. GP1,2 peplomers mediates endothelial cell activation and decreases endothelial barrier function. It mediates activation of primary macrophages. At terminal stages of the viral infection, when its expression is high, GP1,2 down-modulates the expression of various host cell surface molecules that are essential for immune surveillance and cell adhesion [].GP2delta is part of the complex GP1,2delta released by host ADAM17 metalloprotease. This secreted complex may play a role in the pathogenesis of the virus by efficiently blocking the neutralizing antibodies that would otherwise neutralize the virus surface glycoproteins GP1,2. Might therefore contribute to the lack of inflammatory reaction seen during infection in spite the of extensive necrosis and massive virus production. GP1,2delta does not seem to be involved in activation of primary macrophage [].pre-small/secreted glycoprotein sGP seems to possess an anti-inflammatory activity as it can reverse the barrier-decreasing effects of TNF alpha. It might therefore contribute to the lack of inflammatory reaction seen during infection in spite the of extensive necrosis and massive virus production. It does not seem to be involved in activation of primary macrophages. It does not seem to interact specifically with neutrophils [, , , ].
Coronavirus encodes two viroporins, E protein and protein 3a, which act as ion-conductive pores in planar lipid bilayers and are required for maximal SARS-CoV replication and virulence []. In betacoronavirus, this protein plays a role in viral egress via lysosomal trafficking [, ]. Protein 3a from SARS-CoV-2 also blocks autolysosomes formation by binding and sequestering the host component VPS39 for homotypic fusion and protein sorting (HOPS) on late endosomes. This prevents fusion of autophagosomes with lysosomes, disrupting autophagy and facilitating virus egress [].This entry represents protein 3a encoded by Orf3/3a, also known as X1, which forms homotetrameric potassium, sodium or calcium sensitive ion channels (viroporin) and may modulate virus release. It has also been shown to up-regulate expression of fibrinogen subunits FGA, FGBand FGG in host lung epithelial cells [, , , ].3a protein is a pro-apoptosis-inducing protein. It localises to the endoplasmic reticulum (ER)-Golgi compartment. SARS-CoV causes apoptosis of infected cells through NLRP3 inflammasome activation, as ORF3a is a potent activator of the signals required for this activation, pro-IL-1beta gene transcription and protein maturation. This protein also promotes the ubiquitination of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) mediated by its interaction with TNF receptor-associated factor 3 (TRAF3). The expression of ORF3a induces NF-kappa B activation and up-regulates fibrinogen secretion with the consequent high cytokine production [, , , ]. Another apoptosis mechanism described for this protein is the activation of the PERK pathway of unfolded protein response (UPR), which causes phosphorylation of eIF2alpha and leads to reduced translation of cellular proteins as well as the activation of pro-apoptotic downstream effectors (i.e ATF4, CHOP) [].
Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as activation-inducible TNF receptor (AITR), glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR), CD357, or GITR-D, has increased expression upon T-cell activation, and is thought to play a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells []. In inflammatory cells, GITR expression indicates a possible molecular link between steroid use and complicated acute sigmoid diverticulitis; increased MMP-9 expression by GITR signaling might explain morphological changes in the colonic wall in diverticulitis []. Its ligand, GITRL, activates GITR which could then influence the activity of effector and regulatory T cells, participating in the development of several autoimmune and inflammatory diseases, including autoimmune thyroid disease and rheumatoid arthritis [, ]. In systemic lupus erythematosus (SLE) patients, serum GITRL levels are increased compared with healthy controls []. GITR and its ligand, GITRL, are possibly involved in the pathogenesis of primary Sjogren's syndrome (pSS) [].GITR is inactivated during tumor progression in Multiple Myeloma (MM); restoration of GITR expression in GITR deficient MM cells leads to inhibition of MM proliferation and induction of apoptosis, thus playing a pivotal role in MM pathogenesis and disease progression []. Regulatory T-cells (Tregs) in liver tumor up-regulate the expression of GITR compared with Tregs in tumor-free liver tissue and blood []. Regulatory single nucleotide polymorphisms (SNPs) in the promoter regions of the TNFRSF18 gene have been identified in a group of male Gabonese individuals exposed to a wide array of parasitic diseases such as malaria, filariasis and schistosomiasis, and may serve as a basis to study parasite susceptibility in association studies [].This entry represents the N-terminal domain of TNFRSF18. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [, , ].
The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern []. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding []. Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences []. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [, ]. TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis []. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease []. TNF receptor 27 (also known as ectodysplasin A2 receptor (EDA2R) and ectodysplasin receptor, x-linked (XEDAR)) is highly expressed during embryogenesis [], and has been implicated in the development of ectodermal appendages, such as hair follicles, teeth and sweat glands []. Although it lacks a death domain, the receptor can nevertheless induce cell death via activation of caspase 8, and may play a role in the induction of apoptosis during embryonic development and adult life []. A single partial match was also found, , a translated human cDNA sequence that fails to match motif 1.
