Journal
CELL REPORTS
Volume 40, Issue 7, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2022.111225
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Funding
- National Institutes of Health [R01NS098747, R01AI079293, R01AI060025, 2U19 AI089681]
- Biotechnology and Biological Sciences Research Council [BB/V000276/1]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (Fapesp [2016/23618-8]
- Brazilian National Institute of Science and Technology for Vaccines - Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) /Fundacao de Amparo Pesquisa do Estado de Minas Gerais (Fapemig) /Coordenacao de Aperfeicoamento de Pessoal de Ensino [465293/2014-0]
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This study examines the importance of IRAK proteins in TLR4 activation and confirms the essential role of IRAK4 kinase activity in MYD88 signaling. It also reveals the crucial role of the IRAK4 scaffold in integrating MYD88 and TRIF in TLR4 signaling.
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-b (TRIF), a unique adap-tation in the TLR4 response. IRAK4 scaffold is, therefore, essential in integrating MYD88 and TRIF in TLR4 signaling.
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