Cyclophilin A-regulated ubiquitination is critical for RIG-I-mediated antiviral immune responses

  1. Wei Liu
  2. Jing Li
  3. Weinan Zheng
  4. Yingli Shang
  5. Zhendong Zhao
  6. Shanshan Wang
  7. Yuhai Bi
  8. Shuang Zhang
  9. Chongfeng Xu
  10. Ziyuan Duan
  11. Lianfeng Zhang
  12. Yue Lynn Wang
  13. Zhengfan Jiang
  14. Wenjun Liu  Is a corresponding author
  15. Lei Sun  Is a corresponding author
  1. Chinese Academy of Sciences, China
  2. Shandong Agricultural University, China
  3. Chinese Academy of Medical Sciences, China
  4. University of Chicago, United States
  5. School of Life Sciences, Peking University, China

Abstract

RIG-I is a key cytosolic pattern recognition receptor that interacts with MAVS to induce type I interferons (IFNs) against RNA virus infection. In this study, we found that cyclophilin A (CypA), a peptidyl-prolyl cis/trans isomerase, functioned as a critical positive regulator of RIG-I-mediated antiviral immune responses. Deficiency of CypA impaired RIG-I-mediated type I IFN production and promoted viral replication in human cells and mice. Upon Sendai virus infection, CypA increased the interaction between RIG-I and its E3 ubiquitin ligase TRIM25, leading to enhanced TRIM25-mediated K63-linked ubiquitination of RIG-I that facilitated recruitment of RIG-I to MAVS. In addition, CypA and TRIM25 competitively interacted with MAVS, thereby inhibiting TRIM25-induced K48-linked ubiquitination of MAVS. Taken together, our findings reveal an essential role of CypA in boosting RIG-I-mediated antiviral immune responses by controlling the ubiquitination of RIG-I and MAVS.

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Author details

  1. Wei Liu

    CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Jing Li

    CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Weinan Zheng

    CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yingli Shang

    College of Veterinary Medicine, Shandong Agricultural University, Tai'an, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Zhendong Zhao

    CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Shanshan Wang

    CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Yuhai Bi

    CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Shuang Zhang

    CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Chongfeng Xu

    Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Ziyuan Duan

    Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Lianfeng Zhang

    Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Yue Lynn Wang

    Department of Pathology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Zhengfan Jiang

    The Education Ministry Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Wenjun Liu

    CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    For correspondence
    liuwj@im.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
  15. Lei Sun

    CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
    For correspondence
    sunlei362@im.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0141-2093

Funding

National Natural Science Foundation of China (31472178)

  • Lei Sun

National Natural Science Foundation of China (31672531)

  • Lei Sun

Key Research Program of Chinese Academy of Sciences (KSZD-EW-Z-005-001)

  • Wenjun Liu

National Key Technology Support Program of China (2015BAD11B02)

  • Lei Sun

National Natural Science Foundation of China (81621091)

  • Wenjun Liu

National Key Research and Development Program of China (2016YFC1201001)

  • Lei Sun

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The animal research was approved by the Research Ethics Committee of Chinese Academy of Sciences (Permit Number: PZIMCAS2013001), and complied with the Beijing Laboratory Animal Welfare and Ethical Guidelines of the Beijing Administration Committee of Laboratory Animals.

Copyright

© 2017, Liu 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. Wei Liu
  2. Jing Li
  3. Weinan Zheng
  4. Yingli Shang
  5. Zhendong Zhao
  6. Shanshan Wang
  7. Yuhai Bi
  8. Shuang Zhang
  9. Chongfeng Xu
  10. Ziyuan Duan
  11. Lianfeng Zhang
  12. Yue Lynn Wang
  13. Zhengfan Jiang
  14. Wenjun Liu
  15. Lei Sun
(2017)
Cyclophilin A-regulated ubiquitination is critical for RIG-I-mediated antiviral immune responses
eLife 6:e24425.
https://doi.org/10.7554/eLife.24425

Share this article

https://doi.org/10.7554/eLife.24425

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