Identification of optineurin as an interleukin-1 receptor-associated kinase 1-binding protein and its role in regulation of MyD88-dependent signaling.
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 κB (NF-κB) 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-1β-, IRAK1-, and LPS-induced NF-κB activation. Consistently, OPTN deficiency resulted in increased NF-κB activation in response to IL-1β/LPS stimulation. To address the mechanisms underlying the inhibitory effect of OPTN on NF-κB 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-κB 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-κB activation. These results suggest that the IRAK1-binding protein OPTN negatively regulates IL-1β/LPS-induced NF-κB activation by preventing polyubiquitination of TRAF6.
Mesh Terms:
Amino Acid Substitution, Animals, Cysteine Endopeptidases, Deubiquitinating Enzyme CYLD, Eye Proteins, HEK293 Cells, Humans, Interleukin-1 Receptor-Associated Kinases, Lipopolysaccharides, Mice, Mutation, Missense, Myeloid Differentiation Factor 88, NF-kappa B, RAW 264.7 Cells, Signal Transduction, TNF Receptor-Associated Factor 6, Transcription Factor TFIIIA, Tumor Suppressor Proteins, Ubiquitination
Amino Acid Substitution, Animals, Cysteine Endopeptidases, Deubiquitinating Enzyme CYLD, Eye Proteins, HEK293 Cells, Humans, Interleukin-1 Receptor-Associated Kinases, Lipopolysaccharides, Mice, Mutation, Missense, Myeloid Differentiation Factor 88, NF-kappa B, RAW 264.7 Cells, Signal Transduction, TNF Receptor-Associated Factor 6, Transcription Factor TFIIIA, Tumor Suppressor Proteins, Ubiquitination
J. Biol. Chem.
Date: Dec. 20, 2016
PubMed ID: 28882891
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