CD40 ligand (CD40L) is a transmembrane protein belonging to the Tumour Necrosis Factor (TNF) superfamily. It can be found on the surface of B lymphocytes, dendritic cells, follicular dendritic cells, hematopoietic progenitor cells, epithelial cells, and carcinomas []. CD40L is importance for effective interaction with CD40 and the subsequent intracellular signalling []. It is involved in B-cell proliferation and immunoglobulin class switching []. 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.
This entry represents mitogen-activated protein kinase kinase kinase 8 (MAP3K8 or COT or TPL2) (), which plays a role in the cell cycle. MAP3K8 is required for TLR4 activation of the MEK/ERK pathway. MAP3K8 is able to activate NF-kappa-B 1 (NFKB1) by stimulating proteasome-mediated proteolysis of NF-kappa-B 1/p105 []. MAP3K8 forms a ternary complex with NFKB1 and TNIP2 []. MAP3K8 is recruited to the CD40 complex via a mechanism dependent on TRAF-binding sites in CD40 [].
Tumor necrosis factor receptor superfamily member 5 (TNFRSF5), commonly known as CD40 and also as CDW40, p50 or Bp50, is widely expressed in diverse cell types including B lymphocytes, dendritic cells, platelets, monocytes, endothelial cells, and fibroblasts []. It is essential in mediating a wide variety of immune and inflammatory responses, including T cell-dependentimmunoglobulin class switching, memory B cell development, and germinal centre formation [, , , ]. Its natural immunomodulating ligand is CD40L, and a primary defect in the CD40/CD40L system is associated with X-linked hyper-IgM (XHIM) syndrome []. It is also involved in tumorigenesis. The CD40/CD40L system serves as a link between tumorigenesis, atherosclerosis, and the immune system, and offers a potential target for drug therapy for related diseases, such as cancer, atherosclerosis, diabetes mellitus, and immunological rejection [].TNFRSF5/CD40 homologues have been identified in teleosts. The zebrafish CD40 is a type I membrane-bound protein with a sequence pattern of four cysteine-rich domains in its extracellular N-terminal region. The consensus TNFR-associated factor (TRAF)2- and TRAF6-binding motifs in mammalian CD40 are found in the cytoplasmic tail of zebrafish CD40, which indicates similar signal transduction mechanisms to higher vertebrates []. Salmon CD40 and CD40L are widely expressed, particularly in immune tissues, and their importance for the immune response is indicated by their relatively high expression in salmon lymphoid organs and gills [].This entry represents the N-terminal domain of TNFRSF5 from teleosts.
C-type lectin domain family 12 member B (CLEC12B) is a lectin C-type inhibitory receptor that plays a role in myeloid cell function []. CLEC12A (also known as MICL or DCAL-2) is expressed in monocytes, macrophages, and dendritic-cells (DCs). It serves as a functional receptor on DCs and can internalize and collaborate with TLR or CD40 signaling and regulate immune responses [].
Tumor necrosis factor receptor superfamily member 5 (TNFRSF5), commonly known as CD40 and also as CDW40, p50 or Bp50, is widely expressed in diverse cell types including B lymphocytes, dendritic cells, platelets, monocytes, endothelial cells, and fibroblasts []. It is essential in mediating a wide variety of immune and inflammatory responses, including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal centre formation [, , , ]. Its natural immunomodulating ligand is CD40L, and a primary defect in the CD40/CD40L system is associated with X-linked hyper-IgM (XHIM) syndrome []. It is also involved in tumorigenesis; CD40 expression is significantly higher in gastric carcinomas and it is associated with the lymphatic metastasis of cancer cells and their tumor node metastasis (TNM) classification []. Upregulated levels of CD40/CD40L on B cells and T cells may play an important role in the immune pathogenesis of breast cancer []. Consequently, the CD40/CD40L system serves as a link between tumorigenesis, atherosclerosis, and the immune system, and offers a potential target for drug therapy for related diseases, such as cancer, atherosclerosis, diabetes mellitus, and immunological rejection [].This entry represents the N-terminal domain of TNFRSF5. 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)-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 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 [].
