TRIM28 promotes HIV-1 latency by SUMOylating CDK9 and inhibiting P-TEFb

  1. Xiancai Ma
  2. Tao Yang
  3. Yuewen Luo
  4. Liyang Wu
  5. Yawen Jiang
  6. Zheng Song
  7. Ting Pan
  8. Bingfeng Liu
  9. Guangyan Liu
  10. Jun Liu
  11. Fei Yu
  12. Zhangping He
  13. Wanying Zhang
  14. Jinyu Yang
  15. Liting Liang
  16. Yuanjun Guan
  17. Xu Zhang
  18. Linghua Li
  19. Weiping Cai
  20. Xiaoping Tang
  21. Song Gao
  22. Kai Deng
  23. Hui Zhang  Is a corresponding author
  1. Sun Yat-sen University, China
  2. Shenyang Medical College, China
  3. Sun Yat-Sen University Cancer Center, China
  4. Guangzhou 8th People's Hospital, China

Abstract

Comprehensively elucidating the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) latency is a priority to achieve a functional cure. As current 'shock' agents failed to efficiently reactivate the latent reservoir, it is important to discover new targets for developing more efficient latency-reversing agents (LRAs). Here we found that TRIM28 potently suppresses HIV-1 expression by utilizing both SUMO E3 ligase activity and epigenetic adaptor function. Through global site-specific SUMO-MS study and serial SUMOylation assays, we identified that P-TEFb catalytic subunit CDK9 is significantly SUMOylated by TRIM28 with SUMO4. The Lys44, Lys56 and Lys68 residues on CDK9 are SUMOylated by TRIM28, which inhibits CDK9 kinase activity or prevents P-TEFb assembly by directly blocking the interaction between CDK9 and Cyclin T1, subsequently inhibits viral transcription and contributes to HIV-1 latency. The manipulation of TRIM28 and its consequent SUMOylation pathway could be the target for developing LRAs.

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. Xiancai Ma

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Tao Yang

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Yuewen Luo

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Liyang Wu

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Yawen Jiang

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Zheng Song

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Ting Pan

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Bingfeng Liu

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Guangyan Liu

    College of Basic Medical Sciences, Shenyang Medical College, Shenyang, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Jun Liu

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Fei Yu

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Zhangping He

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Wanying Zhang

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Jinyu Yang

    State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Liting Liang

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  16. Yuanjun Guan

    Core Laboratory Platform for Medical Science, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  17. Xu Zhang

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  18. Linghua Li

    Department of Infectious Diseases, Guangzhou 8th People's Hospital, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  19. Weiping Cai

    Department of Infectious Diseases, Guangzhou 8th People's Hospital, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  20. Xiaoping Tang

    Department of Infectious Diseases, Guangzhou 8th People's Hospital, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  21. Song Gao

    State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7427-6681
  22. Kai Deng

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  23. Hui Zhang

    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
    For correspondence
    zhangh92@mail.sysu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3620-610X

Funding

National Special Research Program of China for Important Infectious Diseases (2017ZX10202102)

  • Hui Zhang

Important Key Program of Natural Science Foundation of China (81730060)

  • Hui Zhang

International Collaboration Program of Natural Science Foundation of China and US NIH (81561128007)

  • Hui Zhang

Joint-innovation Program in Healthcare for Special Scientific Research Projects of Guangzhou (201803040002)

  • Hui Zhang

National Special Research Program of China for Important Infectious Diseases (2018ZX10302103)

  • Hui Zhang

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

Ethics

Human subjects: Chronically HIV-1-infected participants sampled by this study were recruited from Department of Infectious Diseases in Guangzhou 8th People's Hospital, Guangzhou. The Ethics Review Board of Sun Yat-Sen University and the Ethics Review Board of Guangzhou 8th People's Hospital approved this study. All the participants were given written informed consent with approval of the Ethics Committees. The enrollment of HIV-1-infected individuals was based on the criteria of prolonged suppression of plasma HIV-1 viremia on cART, which is undetectable plasma HIV-1 RNA levels (less than 50 copies/ml) for a minimum of six months, and having high CD4+ T cell count (at least 350 cells/mm3). Blood samples from healthy individuals were obtained from Guangzhou Blood Center. We did not have any interaction with the healthy individuals or protected information, and therefore no informed consent was required. The statement was also included in the Materials and Methods section.

Reviewing Editor

  1. Jeremy Luban, University of Massachusetts Medical School, United States

Version history

  1. Received: September 28, 2018
  2. Accepted: January 16, 2019
  3. Accepted Manuscript published: January 17, 2019 (version 1)
  4. Version of Record published: February 4, 2019 (version 2)

Copyright

© 2019, Ma 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. Xiancai Ma
  2. Tao Yang
  3. Yuewen Luo
  4. Liyang Wu
  5. Yawen Jiang
  6. Zheng Song
  7. Ting Pan
  8. Bingfeng Liu
  9. Guangyan Liu
  10. Jun Liu
  11. Fei Yu
  12. Zhangping He
  13. Wanying Zhang
  14. Jinyu Yang
  15. Liting Liang
  16. Yuanjun Guan
  17. Xu Zhang
  18. Linghua Li
  19. Weiping Cai
  20. Xiaoping Tang
  21. Song Gao
  22. Kai Deng
  23. Hui Zhang
(2019)
TRIM28 promotes HIV-1 latency by SUMOylating CDK9 and inhibiting P-TEFb
eLife 8:e42426.
https://doi.org/10.7554/eLife.42426

Share this article

https://doi.org/10.7554/eLife.42426

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