The IRAK4 scaffold integrates TLR4-driven TRIF and MYD88 signaling pathways

• Published in: Cell reports (Cambridge) Vol. 40; no. 7; p. 111225
• Main Authors: Pereira, Milton, Durso, Danielle F., Bryant, Clare E., Kurt-Jones, Evelyn A., Silverman, Neal, Golenbock, Douglas T., Gazzinelli, Ricardo T.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 16.08.2022
• Subjects: cell signaling; Gram-negative; innate immunity; IRAK; LPS; macrophage; NF-kB; TLR; Toll-like receptor; TRAF6; CP: Immunology; IRAK; innate immunity; Gram-negative; TRAF6; cell signaling; NF-kB; macrophage; TLR; Toll-like receptor; LPS
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111225

Interleukin-1 receptor-associated kinases (IRAKs) −4, −2, and −1 are involved in transducing signals from Toll-like receptors (TLRs) via the adaptor myeloid differentiation primary-response protein 88 (MYD88). How MYD88/IRAK4/2/1 complexes are formed, their redundancies, and potential non-enzymatic roles are subjects of debate. Here, we examine the hierarchical requirements for IRAK proteins in the context of TLR4 activation and confirmed that the kinase activity of IRAK4 is essential for MYD88 signaling. Surprisingly, the IRAK4 scaffold is required for activation of the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) by both MYD88 and TIR domain-containing adaptor protein inducing IFN-β (TRIF), a unique adaptation in the TLR4 response. IRAK4 scaffold is, therefore, essential in integrating MYD88 and TRIF in TLR4 signaling. [Display omitted] •IRAK1 and IRAK2 are partially redundant in TLR4 signaling, but not in TLR7 signaling•IRAK4 kinase activity is required for TLR4/MYD88 signaling•TRIF and MYD88 require the IRAK4 scaffold for TRAF6 activation•TRIF-mediated TRAF3 activation occurs independently of IRAKs By studying the redundancies of IRAK proteins in Toll-like receptor (TLR) 4 and 7 signaling, Pereira et al. demonstrate a kinase-independent function for IRAK4 in the TRIF pathway. This provides an understanding of how TLR4 signaling triggers the production of inflammatory cytokines upon infections with Gram-negative bacteria.