Identification of optineurin as an interleukin-1 receptor-associated kinase 1-binding protein and its role in regulation of MyD88-dependent signaling.

ABSTRACT: 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 ?B (NF-?B) 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-1?-, IRAK1-, and LPS-induced NF-?B activation. Consistently, OPTN deficiency resulted in increased NF-?B activation in response to IL-1?/LPS stimulation. To address the mechanisms underlying the inhibitory effect of OPTN on NF-?B 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-?B 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-?B activation. These results suggest that the IRAK1-binding protein OPTN negatively regulates IL-1?/LPS-induced NF-?B activation by preventing polyubiquitination of TRAF6.

SUBMITTER: Tanishima M 

PROVIDER: S-EPMC5655504 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature