MyD88 was first described in 1990 as a gene upregulated during IL-6-induced myeloid differentiation. MyD88 was implicated in signaling downstream of IL-1R and mammalian TLRs. The C-terminal TIR (Toll IL-1R) domain mediates the interaction with other TIR domain-containing proteins (receptors or adaptors); the N-terminal death domain (DD) associates with the IRAK family members through homotypic DD interactions. Consistent with these roles, overexpression of the DD of MyD88 leads to spontaneous activation of NFκB and c-Jun N-terminal kinase (JNK), whereas the TIR domain can act as a dominant negative. MyD88-deficient mice were shown to lack responsiveness to lipopolysaccharide (LPS), the ligand for TLR4. Several inactivating mutations in MyD88 have also been identified in humans with recurrent infections with pyogenic bacteria. These mutations, as well as some rare missense polymorphisms, are associated with reduced IRAK4 activation, leading to impaired responses through TLRs and IL-1 family members. . Phosphorylated IRAKs 1 and 2 interact with the E3 ubiquitin ligase TNF receptor–associated factor 6 (TRAF6), via their TRAF binding domains. TRAF6 ultimately recruits TAK1-binding protein 2 (TAB2) and activates TAB2-associated TGFbactivated kinase 1 (TAK1), which promotes cell survival through activation of both the canonical NF-kB (p50–p65) pathway and the mitogen-activated protein kinase (MAPK) pathway.

References

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