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

Milton Pereira | Danielle F Durso | Clare E Bryant | Evelyn A Kurt-Jones | Neal Silverman | Douglas T Golenbock | Ricardo T Gazzinelli
Cell reports | 2022

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.

Pubmed ID: 35977521 RIS Download

Research resources used in this publication

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Associated grants

  • Agency: NIAID NIH HHS, United States
    Id: R56 AI060025
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI079293
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM054060
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI052455
  • Agency: NIAID NIH HHS, United States
    Id: U24 AI082663
  • Agency: NIAID NIH HHS, United States
    Id: U19 AI089681
  • Agency: NIAID NIH HHS, United States
    Id: R21 AI150546
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI060025
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS098747
  • Agency: Biotechnology and Biological Sciences Research Council, United Kingdom
    Id: BB/V000276/1

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