IRAK-M mediates Toll-like receptor/IL-1R-induced NF[kappa]B activation and cytokine production

• Published in: The EMBO journal Vol. 32; no. 4; p. 583
• Main Authors: Zhou, Hao, Yu, Minjia, Fukuda, Koichi, Im, Jinteak, Yao, Peng, Cui, Wei, Bulek, Katarzyna, Zepp, Jarod, Wan, Youzhong, Whan Kim, Tae, Yin, Weiguo, Ma, Victoria, Thomas, James, Gu, Jun, Wang, Jian-an, Dicorleto, Paul E, Fox, Paul L, Qin, Jun, Li, Xiaoxia
• Format: Journal Article
• Language: English
• Published: Heidelberg Blackwell Publishing Ltd 20.02.2013
• Subjects: Cytokines; Gene expression; Immunology; Kinases; Molecular biology; Signal transduction
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2013.2

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. [PUBLICATION ABSTRACT]