Myeloid differentiation primary response 88 (MyD88)–Interleukin-1 receptor-associated kinase (IRAK)–TNF receptor-associated factor 6 (TRAF6) signaling axis (MyD88–IRAK–TRAF6 axis)

The MyD88–IRAK–TRAF6 signaling axis is a fundamental pathway in the innate immune system that transduces signals from Toll-like receptors (TLRs) and Interleukin-1 receptors (IL-1Rs). Upon receptor activation, the adaptor protein Myeloid differentiation primary response 88 (MyD88) recruits Interleukin-1 receptor-associated kinases (IRAKs), primarily IRAK4 and IRAK1, to form a supramolecular complex known as the Myddosome. This complex subsequently recruits the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6), which facilitates the activation of downstream effectors such as the NF-κB and MAPK pathways. These pathways drive the expression of pro-inflammatory cytokines and mediators essential for the immune response. Dysregulation or constitutive activation of this axis, often through gain-of-function mutations like MYD88 L265P, is a hallmark of several B-cell malignancies and chronic inflammatory conditions. Consequently, this axis has become a major focus for drug development, with therapeutic candidates including small-molecule inhibitors of IRAK4 kinase activity, IRAK4 degraders, and inhibitors of MyD88 or TRAF6 protein-protein interactions. Clinical candidates like emavusertib and KT-474 are currently being evaluated for their efficacy in treating both hematologic cancers and autoimmune disorders. While targeting this axis offers significant therapeutic potential, it also carries risks of immunosuppression and increased susceptibility to specific bacterial infections.

Other names

MyddosomeMyD88-dependent signaling pathwayTLR/IL-1R signaling axisMyD88-IRAK-TRAF6 pathway

Inhibition of IRAK4 kinase activity, targeted degradation of IRAK4 protein, and disruption of protein-protein interactions within the MyD88-IRAK-TRAF6 complex to prevent downstream NF-κB and MAPK signaling.