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Ubiquitination and degradation of NF90 by Tim-3 inhibits antiviral innate immunity.


ABSTRACT: Nuclear factor 90 (NF90) is a novel virus sensor that serves to initiate antiviral innate immunity by triggering stress granule (SG) formation. However, the regulation of the NF90-SG pathway remains largely unclear. We found that Tim-3, an immune checkpoint inhibitor, promotes the ubiquitination and degradation of NF90 and inhibits NF90-SG-mediated antiviral immunity. Vesicular stomatitis virus (VSV) infection induces the up-regulation and activation of Tim-3 in macrophages, which in turn recruit the E3 ubiquitin ligase TRIM47 to the zinc finger domain of NF90 and initiate a proteasome-dependent degradation via K48-linked ubiquitination at Lys297. Targeted inactivation of Tim-3 enhances the NF90 downstream SG formation by selectively increasing the phosphorylation of protein kinase R and eukaryotic translation initiation factor 2α, the expression of SG markers G3BP1 and TIA-1, and protecting mice from VSV challenge. These findings provide insights into the crosstalk between Tim-3 and other receptors in antiviral innate immunity and its related clinical significance.

SUBMITTER: Dou S 

PROVIDER: S-EPMC8225388 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Ubiquitination and degradation of NF90 by Tim-3 inhibits antiviral innate immunity.

Dou Shuaijie S   Li Guoxian G   Li Ge G   Hou Chunmei C   Zheng Yang Y   Tang Lili L   Gao Yang Y   Mo Rongliang R   Li Yuxiang Y   Wang Renxi R   Shen Beifen B   Zhang Jun J   Han Gencheng G  

eLife 20210610


Nuclear factor 90 (NF90) is a novel virus sensor that serves to initiate antiviral innate immunity by triggering stress granule (SG) formation. However, the regulation of the NF90-SG pathway remains largely unclear. We found that Tim-3, an immune checkpoint inhibitor, promotes the ubiquitination and degradation of NF90 and inhibits NF90-SG-mediated antiviral immunity. Vesicular stomatitis virus (VSV) infection induces the up-regulation and activation of Tim-3 in macrophages, which in turn recrui  ...[more]

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