USP19 Inhibits TNF-?- and IL-1?-Triggered NF-?B Activation by Deubiquitinating TAK1.
The dynamic regulations of ubiquitination and deubiquitination play important roles in TGF-?-activated kinase 1 (TAK1)-mediated NF-?B activation, which regulates various physiological and pathological events. We identified ubiquitin-specific protease (USP)19 as a negative regulator of TNF-?- and IL-1?-triggered NF-?B activation by deubiquitinating TAK1. Overexpression of USP19 but not its enzymatic inactive ... mutant inhibited TNF-?- and IL-1?-triggered NF-?B activation and transcription of downstream genes, whereas USP19 deficiency had the opposite effects. Usp19-/- mice produced higher levels of inflammatory cytokines and were more susceptible to TNF-?- and IL-1?-triggered septicemia death compared with their wild-type littermates. Mechanistically, USP19 interacted with TAK1 in a TNF-?- or IL-1?-dependent manner and specifically deconjugated K63- and K27-linked polyubiquitin chains from TAK1, leading to the impairment of TAK1 activity and the disruption of the TAK1-TAB2/3 complex. Our findings provide new insights to the complicated molecular mechanisms of the attenuation of the inflammatory response.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Disease Susceptibility, Endopeptidases, HEK293 Cells, Humans, Immune Tolerance, Inflammation, Interleukin-1beta, MAP Kinase Kinase Kinases, Mice, Mice, Knockout, NF-kappa B, Protein Binding, RNA, Small Interfering, Sepsis, Tumor Necrosis Factor-alpha, Ubiquitination
Adaptor Proteins, Signal Transducing, Animals, Disease Susceptibility, Endopeptidases, HEK293 Cells, Humans, Immune Tolerance, Inflammation, Interleukin-1beta, MAP Kinase Kinase Kinases, Mice, Mice, Knockout, NF-kappa B, Protein Binding, RNA, Small Interfering, Sepsis, Tumor Necrosis Factor-alpha, Ubiquitination
J. Immunol.
Date: Dec. 01, 2018
PubMed ID: 31127032
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