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 of the NF90 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 lethal VSV challenge. These findings provide insights into the crosstalk between Tim-3 and other receptors in antiviral innate immunity and its related clinical significance.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Funding support 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).
Abbreviations
- NF90
- Nuclear Factor 90
- SGs
- Stress granules
- VSV
- Vesicular Stomatitis Virus
- PKR
- Protein kinase R
- (eIF2α)
- the eukaryotic translation initiation factor 2α
- G3BP1
- Ras-GAP SH3-binding protein-1
- TIA-1
- T-cell intracellular antigen-1
- TRIM47
- tripartite motif-containing protein 47
