| First Author | Wu X | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 4115 |
| PubMed ID | 31511519 | Mgi Jnum | J:279314 |
| Mgi Id | MGI:6362215 | Doi | 10.1038/s41467-019-12145-1 |
| Citation | Wu X, et al. (2019) Regulation of TRIF-mediated innate immune response by K27-linked polyubiquitination and deubiquitination. Nat Commun 10(1):4115 |
| abstractText | TIR domain-containing adaptor inducing interferon-beta (TRIF) is an essential adaptor protein required for innate immune responses mediated by Toll-like receptor (TLR) 3- and TLR4. Here we identify USP19 as a negative regulator of TLR3/4-mediated signaling. USP19 deficiency increases the production of type I interferons (IFN) and proinflammatory cytokines induced by poly(I:C) or LPS in vitro and in vivo. Usp19(-/-) mice have more serious inflammation after poly(I:C) or LPS treatment, and are more susceptible to inflammatory damages and death following Salmonella typhimurium infection. Mechanistically, USP19 interacts with TRIF and catalyzes the removal of TRIF K27-linked polyubiquitin moieties, thereby impairing the recruitment of TRIF to TLR3/4. In addition, the RING E3 ubiquitin ligase complex Cullin-3-Rbx1-KCTD10 catalyzes K27-linked polyubiquitination of TRIF at K523, and deficiency of this complex inhibits TLR3/4-mediated innate immune signaling. Our findings thus reveal TRIF K27-linked polyubiquitination and deubiquitination as a critical regulatory mechanism of TLR3/4-mediated innate immune responses. |
