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

Author

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  • Xin Wu

    (Zhongnan Hospital of Wuhan University, Wuhan University
    Wuhan University)

  • Caoqi Lei

    (Wuhan University)

  • Tian Xia

    (Zhongnan Hospital of Wuhan University, Wuhan University
    Wuhan University)

  • Xuan Zhong

    (Zhongnan Hospital of Wuhan University, Wuhan University
    Wuhan University)

  • Qing Yang

    (Zhongnan Hospital of Wuhan University, Wuhan University)

  • Hong-Bing Shu

    (Zhongnan Hospital of Wuhan University, Wuhan University
    Wuhan University)

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.

Suggested Citation

  • Xin Wu & Caoqi Lei & Tian Xia & Xuan Zhong & Qing Yang & Hong-Bing Shu, 2019. "Regulation of TRIF-mediated innate immune response by K27-linked polyubiquitination and deubiquitination," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12145-1
    DOI: 10.1038/s41467-019-12145-1
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