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

Accepted version
Peer-reviewed

Type

Article

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Authors

Pereira, Milton 
Durso, Danielle F 
Bryant, Clare E 
Kurt-Jones, Evelyn A 
Silverman, Neal 

Abstract

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.

Description

Keywords

Journal Title

Cell Rep

Conference Name

Journal ISSN

2211-1247
2211-1247

Volume Title

Publisher

Elsevier BV
Sponsorship
BBSRC (BB/V000276/1)
BBSRC