| First Author | Zhou H | Year | 2013 |
| Journal | EMBO J | Volume | 32 |
| Issue | 4 | Pages | 583-96 |
| PubMed ID | 23376919 | Mgi Jnum | J:206904 |
| Mgi Id | MGI:5553230 | Doi | 10.1038/emboj.2013.2 |
| Citation | Zhou H, et al. (2013) IRAK-M mediates Toll-like receptor/IL-1R-induced NFkappaB activation and cytokine production. EMBO J 32(4):583-96 |
| abstractText | 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 NFkappaB 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 NFkappaB 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 IkappaBalpha), 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 NFkappaB activation to produce inhibitory molecules as a negative feedback for the pathway, while exerting inhibitory effect on translational control of cytokines and chemokines. |
