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

eLife

Yuxiang Li¹  Beifen Shen¹  Gencheng Han¹  Yang Gao¹  Rongliang Mo¹  Ge Li¹  Lili Tang¹  Chunmei Hou¹  Shuaijie Dou²  Renxi Wang³  Guoxian Li⁴  Yang Zheng⁵  Jun Zhang⁶ 

[1] Beijing Institute of Basic Medical Sciences, Beijing, China;Beijing Institute of Basic Medical Sciences, Beijing, China;Anhui Medical University, Hefei, China;Beijing Institute of Basic Medical Sciences, Beijing, China;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;Beijing Institute of Basic Medical Sciences, Beijing, China;Institute of Immunology, Medical School of Henan University, Kaifeng, China;Department of Oncology, First Hospital of Jilin University, Changchun, China;Institute of Immunology, Medical School of Henan University, Kaifeng, China;

关键词: Tim-3;    virus sensor;    NF90;    ubiquitination;    antiviral innate immunity;    Mouse;   

DOI  :  10.7554/eLife.66501

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY