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

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

  • Elife. 2021 Jun 10;10:e66501. doi: 10.7554/eLife.66501.
Shuaijie Dou # 1 2,  Guoxian Li # 1 3,  Ge Li # 1,  Chunmei Hou 1,  Yang Zheng 4,  Lili Tang 1,  Yang Gao 1,  Rongliang Mo 1,  Yuxiang Li 1,  Renxi Wang 1 5,  Beifen Shen 1,  Jun Zhang 3,  Gencheng Han 1
Affiliations

Affiliations

  • 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.
PMID: 34110282 DOI: 10.7554/eLife.66501
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.

Keywords

NF90; Tim-3; antiviral innate immunity; immunology; inflammation; mouse; ubiquitination; virus sensor.

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