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

Xin Wu, Caoqi Lei, Tian Xia, Xuan Zhong, Qing Yang and Hong-Bing Shu ()
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Xin Wu: Zhongnan Hospital of Wuhan University, Wuhan University
Caoqi Lei: Wuhan University
Tian Xia: Zhongnan Hospital of Wuhan University, Wuhan University
Xuan Zhong: Zhongnan Hospital of Wuhan University, Wuhan University
Qing Yang: Zhongnan Hospital of Wuhan University, Wuhan University
Hong-Bing Shu: Zhongnan Hospital of Wuhan University, Wuhan University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12145-1

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