Myeloid differentiation primary responseprotein MyD88 is an intracellular adaptor protein that has an essential role in innate immune signalling. It is vital for the proper responses of interleukin-1 and interleukin-18 and nearly all toll-like receptors (except TLR3) in the activation of transcription factors NF-kappa B and AP-1 followed by the induction of pro-inflammatory genes []. MyD88 contains a TIR (Toll/Interleukin-1 receptor) domain and a death domain []. The TIR domain is important for the protein's interaction with receptors, while the death domain is involved in signal transduction. For example, MyD88 interacts with IL-1R-associated kinase (IRAK)-4 through its death domain, and in turn, IRAK-4 activates other members of the IRAK family, like IRAK-1 [].Defects in MYD88 are the cause of MYD88 deficiency [], also known as as recurrent pyogenic bacterial infections due to MYD88 deficiency.
Toll-like receptor 7 (TLR7) is a key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR7 is a nucleotide-sensing TLR, which is activated by single-stranded RNA, acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response [, ].
Toll-like receptor 1 (TLR1) participates in the innate immune response to microbial agents. TLR1 cooperates with TLR2 to mediate the innate immune response to bacterial lipoproteins or lipopeptides [, ]. It acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.
This entry represents the Death Domain (DD) of Myeloid Differentiation primary response protein 88 (MyD88). MyD88 is an adaptor protein involved in interleukin-1 receptor (IL-1R)- and Toll-like receptor (TLR)-induced activation of nuclear factor-kappaB (NF-kB) and mitogen activated protein kinase pathways that lead to the induction of proinflammatory cytokines []. It is a key component in the signaling pathway of pathogen recognition in the innate immune system. MyD88 contains an N-terminal DD and a C-terminal Toll/IL-1 Receptor (TIR) homology domain that mediates interaction with TLRs and IL-1R [].In general, DDs 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 [].
Toll-like receptor 10 (TLR10) participates in the innate immune response to microbial agents. The human TLR family consist of numerous members, which recognise a wide variety of pathogen-associated molecular patterns. No ligand has yet been reported for TLR10, thus it remains the only orphanfamily member []. It acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. TLR10 has been shown to form homodimers and to interact with TLRs 1 and 2 [].
Toll-like receptor 9 (TLR9) is a key component of innate and adaptive immunity [, ]. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR9 is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides, which is more abundant in bacterial genomes or viral DNA compared to the vertebrate genomes [, , , ]. It acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. TLR9 controls lymphocyte response to Helicobacter infection [].
Interleukin-1 receptor-associated kinase-like 2 (IRAK2) is a critical mediator of TLR/IL1-R signalling [, ]. It is required for production of pro-inflammatory cytokines [, ].All IRAKs are multidomain proteins, consisting of a conserved N-terminal death domain (DD) and a central kinase domain (KD). The DD is a protein interaction motif implicated in binding to the adaptor protein MyD88 []. IRAK2 lacks an active kinase domain, as a critical residue in the kinase domain has changed [].
Toll-like receptor 6 (TLR6) participates in the innate immune response to Gram-positive bacteria and fungi. TLRs recognize specific molecular patterns present only in micro-organisms. TLR1 and TLR6 are involved in the discrimination of a subtle difference between triacyl and diacyl lipopeptides through interaction with TLR2 []. Cooperatively with TLR2, TLR6 recognises mycoplasmal macrophage-activating lipopeptide-2 (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and Borrelia burgdorferi outer surface protein A lipoprotein (OspA-L) []. TLR6 acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response [].
Toll-like receptor 2 (TLR2) is a member of the Toll-like receptor (TLR) family, which plays a role in activation of innate immunity and pathogen recognition []. It helps mediate the innate immune response to bacterial lipoproteins and other microbial cell wall components, acting via MyD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response [, , , ]. TLR2 in association with TLR1 or TLR6 is essential for recognising bacterial lipoproteins and lipopeptides [, ]. It also promotes apoptosis in response to lipoproteins [].Genetic variations in TLR2 are associated with susceptibility to leprosy, a chronic disease associated with depressed cellular (but not humoral) immunity [, ].
Toll-like receptor 8 (TLR8) is a key component of innate and adaptive immunity [, , ]. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. It acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response []. TLR8 has been shown to recognise different types of ligands such as viral or bacterial ssRNA, as well as small synthetic molecules. Activation by ligands is species-specific, varying among non-rodents and rodents [, ].
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 [].
