IRAK-M mediates Toll-like receptor/IL-1R-induced NFκB activation and cytokine production

Hao Zhou, Minjia Yu, Koichi Fukuda, Jinteak Im, Peng Yao, Wei Cui, Katarzyna Bulek, Jarod Zepp, Youzhong Wan, Tae Whan Kim, Weiguo Yin, Victoria Ma, James Thomas, Jun Gu, Jian An Wang, Paul E. Dicorleto, Paul L. Fox, Jun Qin, Xiaoxia Li

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

Toll-like receptors transduce their signals through the adaptor molecule MyD88 and members of the IL-1R-associated kinase family (IRAK-1, 2, M and 4). IRAK-1 and IRAK-2, known to form Myddosomes with MyD88-IRAK-4, mediate TLR7-induced TAK1-dependent NFκB activation. IRAK-M was previously known to function as a negative regulator that prevents the dissociation of IRAKs from MyD88, thereby inhibiting downstream signalling. However, we now found that IRAK-M was also able to interact with MyD88-IRAK-4 to form IRAK-M Myddosome to mediate TLR7-induced MEKK3-dependent second wave NFκB activation, which is uncoupled from post-transcriptional regulation. As a result, the IRAK-M-dependent pathway only induced expression of genes that are not regulated at the post-transcriptional levels (including inhibitory molecules SOCS1, SHIP1, A20 and IκBα), exerting an overall inhibitory effect on inflammatory response. On the other hand, through interaction with IRAK-2, IRAK-M inhibited TLR7-mediated production of cytokines and chemokines at translational levels. Taken together, IRAK-M mediates TLR7-induced MEKK3-dependent second wave NFκB activation to produce inhibitory molecules as a negative feedback for the pathway, while exerting inhibitory effect on translational control of cytokines and chemokines.

Original languageEnglish (US)
Pages (from-to)583-596
Number of pages14
JournalEMBO Journal
Volume32
Issue number4
DOIs
StatePublished - Feb 20 2013

Keywords

  • IRAK
  • Toll-like receptor
  • myddosome
  • signalling

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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