Ubiquitination and degradation of NF90 by Tim-3 inhibits antiviral innate immunity
- Beijing Institute of Basic and Medical Sciences, China
- First hospital of Jilin University, China
- Beijing Institute of Basic Medical Sciences, China
- Medical School of Henan University,, China
Abstract
Nuclear Factor 90 (NF90) is a novel virus sensor that serves to initiate antiviral innate immunity by triggering the stress granules (SGs) formation. However, the regulation of the NF90-SGs pathway remain largely unclear. We found that Tim-3, an immune checkpoint inhibitor, promotes the ubiquitination and degradation of NF90 and inhibits NF90-SGs mediated antiviral immunity. Vesicular Stomatitis Virus (VSV) infection induces the up-regulation and activation of Tim-3 in macrophages which in turn recruited the E3 ubiquitin ligase TRIM47 to the zinc finger domain of NF90 and initiated a proteasome-dependent degradation via K48-linked ubiquitination at Lys297. Targeted inactivation of the Tim-3 enhances the NF90 downstream SGs formation by selectively increasing the phosphorylation of PKR and eIF2a, the expression of SGs markers G3BP1 and TIA-1, and protected 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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
This work was supported by the National Natural Sciences Foundation of China (grants no. 81971473, 81771684), and the Beijing Natural Sciences Foundation (grant no.7192145).
Ethics
Animal experimentation: The protocol was approved by the Ethics Committee of Animal Experiments of the Beijing Institute of Brain Sciences（ (IACUC-DWZX-2018-645). All efforts were made to minimize suffering.
Copyright
© 2021, Dou et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Ubiquitination and degradation of NF90 by Tim-3 inhibits antiviral innate immunity
eLife 10:e66501.
https://doi.org/10.7554/eLife.66501
