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

  1. Shuaijie Dou
  2. Guoxian Li
  3. Ge Li
  4. Chunmei Hou
  5. Yang Zheng
  6. Lili Tang
  7. Yang Gao
  8. Rongliang Mo
  9. Yuxiang Li
  10. Renxi Wang  Is a corresponding author
  11. Beifen Shen
  12. Jun Zhang  Is a corresponding author
  13. Gencheng Han  Is a corresponding author
  1. Beijing Institute of Basic and Medical Sciences, China
  2. First hospital of Jilin University, China
  3. Beijing Institute of Basic Medical Sciences, China
  4. 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.

Article and author information

Author details

  1. Shuaijie Dou

    Immunology, Beijing Institute of Basic and Medical Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Guoxian Li

    Immunology, Beijing Institute of Basic and Medical Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Ge Li

    Immunology, Beijing Institute of Basic and Medical Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Chunmei Hou

    Immunology, Beijing Institute of Basic and Medical Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Yang Zheng

    4.Department of Oncology,, First hospital of Jilin University, Department of Oncology,, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Lili Tang

    Immunology, Beijing Institute of Basic and Medical Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Yang Gao

    Immunology, Beijing Institute of Basic and Medical Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Rongliang Mo

    Immunology, Beijing Institute of Basic and Medical Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Yuxiang Li

    Immunology, Beijing Institute of Basic and Medical Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Renxi Wang

    Laboratory of Immunology, Beijing Institute of Basic Medical Sciences, Beijing, China
    For correspondence
    wang_renxi@hotmail.com
    Competing interests
    The authors declare that no competing interests exist.
  11. Beifen Shen

    Immunology, Beijing Institute of Basic and Medical Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Jun Zhang

    Institute of Immunology,, Medical School of Henan University,, Kaifeng, China
    For correspondence
    zhangjun@henu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
  13. Gencheng Han

    Immunology, Beijing Institute of Basic and Medical Sciences, Beijing, China
    For correspondence
    genchenghan@163.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1408-878X

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.

Reviewing Editor

  1. John W Schoggins, University of Texas Southwestern Medical Center, United States

Version history

  1. Received: January 13, 2021
  2. Accepted: June 8, 2021
  3. Accepted Manuscript published: June 10, 2021 (version 1)
  4. Version of Record published: June 24, 2021 (version 2)
  5. Version of Record updated: June 29, 2021 (version 3)

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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  1. Shuaijie Dou
  2. Guoxian Li
  3. Ge Li
  4. Chunmei Hou
  5. Yang Zheng
  6. Lili Tang
  7. Yang Gao
  8. Rongliang Mo
  9. Yuxiang Li
  10. Renxi Wang
  11. Beifen Shen
  12. Jun Zhang
  13. Gencheng Han
(2021)
Ubiquitination and degradation of NF90 by Tim-3 inhibits antiviral innate immunity
eLife 10:e66501.
https://doi.org/10.7554/eLife.66501

Share this article

https://doi.org/10.7554/eLife.66501

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