MyD88

MYD88, or myeloid differentiation primary response gene 88, is a human gene that encodes an adaptor protein essential for signaling downstream of most Toll-like receptors (TLRs) and IL-1 receptors. Located on chromosome 3p22.2, the MYD88 gene produces a 296‑amino‑acid protein featuring an N‑terminal death domain and a C‑terminal TIR (Toll/IL‑1 receptor) domain. The death and TIR domains enable MyD88 to recruit IRAK kinases and propagate signaling to NF‑κB and MAP kinases, ultimately driving transcription of pro-inflammatory cytokines such as IL‑6, TNF‑α, and IL‑1β.

Signaling through MyD88 is central to the rapid innate immune response. Upon ligand binding to most TLRs or IL‑1 receptors, MyD88 is recruited via its TIR domain, then engages IRAK4 and IRAK1, leading to TRAF6 activation and downstream activation of TAK1, IKK, and MAPKs. This results in inflammatory gene expression and is complemented by MyD88’s role in type I interferon production in plasmacytoid dendritic cells via certain TLR pathways.

Clinical relevance: Loss-of-function mutations in MYD88 cause a primary immunodeficiency characterized by increased susceptibility to pyogenic bacterial infections. Conversely, gain-of-function mutations and constitutive signaling through MyD88 contribute to autoinflammatory states and certain B‑cell malignancies. The most notable somatic mutation is L265P, found in a large proportion of Waldenström’s macroglobulinemia and in activated B-cell–type diffuse large B-cell lymphoma, where it promotes constitutive NF‑κB signaling.

Regulation and isoforms: MyD88 activity is tightly regulated; an inhibitory splice variant, MyD88-S, lacks full IRAK recruitment and can modulate signaling. The protein is evolutionarily conserved across mammals.