| First Author | Tanishima M | Year | 2017 |
| Journal | J Biol Chem | Volume | 292 |
| Issue | 42 | Pages | 17250-17257 |
| PubMed ID | 28882891 | Mgi Jnum | J:246096 |
| Mgi Id | MGI:5921167 | Doi | 10.1074/jbc.M117.813899 |
| Citation | Tanishima M, et al. (2017) Identification of optineurin as an interleukin-1 receptor-associated kinase 1-binding protein and its role in regulation of MyD88-dependent signaling. J Biol Chem 292(42):17250-17257 |
| abstractText | Upon stimulation of toll-like receptors with various microbial ligands, induction of a variety of inflammatory genes is elicited by activation of a myeloid differentiation primary-response protein 88 (MyD88)-dependent signaling pathway. Interleukin-1 (IL-1) receptor-associated kinase 1 (IRAK1) plays an essential role in this pathway by activating nuclear factor kappaB (NF-kappaB) and mitogen-activated kinases (MAPKs). Here, we identified optineurin (OPTN) as an IRAK1-binding protein by yeast two-hybrid screening using IRAK1 as bait. A C-terminal fragment of OPTN harboring a ubiquitin-binding domain was co-immunoprecipitated with IRAK1. In reporter analyses, overexpression of OPTN inhibited IL-1beta-, IRAK1-, and LPS-induced NF-kappaB activation. Consistently, OPTN deficiency resulted in increased NF-kappaB activation in response to IL-1beta/LPS stimulation. To address the mechanisms underlying the inhibitory effect of OPTN on NF-kappaB signaling, we focused on tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which is an adaptor protein of IRAK1 and upon polyubiquitination plays a crucial role during NF-kappaB activation. Overexpression of OPTN prevented TRAF6 polyubiquitination. Furthermore, OPTN H486R mutant, which is unable to recruit the deubiquitinase CYLD, failed to inhibit IRAK1-induced NF-kappaB activation. These results suggest that the IRAK1-binding protein OPTN negatively regulates IL-1beta/LPS-induced NF-kappaB activation by preventing polyubiquitination of TRAF6. |
