Regulation of TRIF-mediated innate immune response by K27-linked polyubiquitination and deubiquitination
Regulation of TRIF-mediated innate immune response by K27-linked polyubiquitination and deubiquitination
复制标题
通过 K27 连接的多聚泛素化和去泛素化调节 TRIF 介导的先天免疫反应
DOI：
10.1038/s41467-019-12145-1
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发表时间：
2019-09-11
影响因子：
16.6
通讯作者：
Shu, Hong-Bing
中科院分区：
文献类型：
--
作者：
Wu, Xin;Lei, Caoqi;Shu, Hong-Bing
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 followingSalmonella typhimuriuminfection. 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.
