| First Author | Lei CQ | Year | 2019 |
| Journal | J Immunol | Volume | 203 |
| Issue | 1 | Pages | 259-268 |
| PubMed ID | 31127032 | Mgi Jnum | J:276968 |
| Mgi Id | MGI:6315799 | Doi | 10.4049/jimmunol.1900083 |
| Citation | Lei CQ, et al. (2019) USP19 Inhibits TNF-alpha- and IL-1beta-Triggered NF-kappaB Activation by Deubiquitinating TAK1. J Immunol 203(1):259-268 |
| abstractText | The dynamic regulations of ubiquitination and deubiquitination play important roles in TGF-beta-activated kinase 1 (TAK1)-mediated NF-kappaB activation, which regulates various physiological and pathological events. We identified ubiquitin-specific protease (USP)19 as a negative regulator of TNF-alpha- and IL-1beta-triggered NF-kappaB activation by deubiquitinating TAK1. Overexpression of USP19 but not its enzymatic inactive mutant inhibited TNF-alpha- and IL-1beta-triggered NF-kappaB 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-alpha- and IL-1beta-triggered septicemia death compared with their wild-type littermates. Mechanistically, USP19 interacted with TAK1 in a TNF-alpha- or IL-1beta-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. |
