MyD88dependent

MyD88-dependent signaling refers to a major arm of the innate immune response in which the adaptor protein MyD88 transduces signals from most Toll-like receptors and from the IL-1 receptor family. Activation by microbial ligands leads to rapid transcription of pro-inflammatory genes and recruitment of immune cells. The pathway is typically contrasted with the MyD88-independent or TRIF-dependent pathway used by a subset of receptors to induce type I interferons.

Upon receptor engagement, MyD88 is recruited via the TIR domain and in many cases forms a complex with IRAK4 and IRAK1 through death domain interactions. IRAK4 phosphorylates IRAK1, and the signaling complex associates with TRAF6. This activates TAK1, which in turn triggers the IKK complex and MAP kinases. NF-κB and AP-1 are activated and translocate to the nucleus, driving transcription of cytokines such as TNF, IL-6, IL-12, and IL-1β, as well as chemokines. IL-1R family members also signal through MyD88 to amplify the inflammatory response. Not all TLRs rely solely on MyD88; TLR4, for example, can engage both MyD88-dependent and TRIF-dependent signaling depending on cellular compartment and adaptor usage; the TRIF arm predominantly induces IRF3/7 and type I interferon responses.

MyD88-dependent signaling is tightly regulated by negative feedback mechanisms, including A20, IRAK-M, SOCS proteins, and others, to prevent excessive inflammation. Genetic defects in MyD88 or IRAK4 cause increased susceptibility to severe bacterial infections in humans, underscoring the pathway’s role in host defense. The pathway’s activity is also implicated in inflammatory and autoimmune diseases when dysregulated.