Regulation of TRIF-mediated innate immune response by K27-linked polyubiquitination and deubiquitination

TIR domain-containing adaptor inducing interferon-β (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...

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Veröffentlicht in:Nature communications 2019-09, Vol.10 (1), p.4115-14, Article 4115
Hauptverfasser: Wu, Xin, Lei, Caoqi, Xia, Tian, Zhong, Xuan, Yang, Qing, Shu, Hong-Bing
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Sprache:eng
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Zusammenfassung:TIR domain-containing adaptor inducing interferon-β (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. TRIF is an important adaptor protein for mediating Toll-like receptor (TLR) 3 and TLR4 signaling. Here the authors show that the deubiquitinating enzymes USP19, as well as the E3 ubiquitin ligase complex Cullin-3-Rbx1-KCTD10, modulates TRIF K523 ubiquitination and thereby TRIF recruitment to TLR3/4 to control innate immunity.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-019-12145-1