Ubiquitination and degradation of NF90 by Tim-3 inhibits antiviral innate immunity
- Elife. 2021 Jun 10;10:e66501. doi: 10.7554/eLife.66501.
- 1. Beijing Institute of Basic Medical Sciences, Beijing, China.
- 2. Anhui Medical University, Hefei, China.
- 3. Institute of Immunology, Medical School of Henan University, Kaifeng, China.
- 4. Department of Oncology, First Hospital of Jilin University, Changchun, China.
- 5. Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China.
- # Contributed equally.
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.