USP19 Inhibits TNF-α– and IL-1β–Triggered NF-κB Activation by Deubiquitinating TAK1

: The dynamic regulations of ubiquitination and deubiquitination play important roles in TGF-β-activated kinase 1 (TAK1)-mediated NF-κB activation, which regulates various physiological and pathological events. We identified ubiquitin-specific protease (USP)19 as a negative regulator of TNF-α- and IL-1β-triggered NF-κB activation by deubiquitinating TAK1. Overexpression of USP19 but not its enzymatic inactive mutant inhibited TNF-α- and IL-1β-triggered NF-κB 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-α- and IL-1β-triggered septicemia death compared with their wild-type littermates. Mechanistically, USP19 interacted with TAK1 in a TNF-α- or IL-1β-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.