Journal
EMBO JOURNAL
Volume 32, Issue 4, Pages 583-596Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/emboj.2013.2
Keywords
IRAK; myddosome; signalling; Toll-like receptor
Categories
Funding
- NIH [2PO1 HL 029582-26A1, 2PO1CA062220-16A1]
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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 NF kappa B 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 NF kappa B 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 I kappa B alpha), 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 NF kappa B activation to produce inhibitory molecules as a negative feedback for the pathway, while exerting inhibitory effect on translational control of cytokines and chemokines. The EMBO Journal (2013) 32, 583-596. doi: 10.1038/emboj.2013.2; Published online 1 February 2013
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