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PRMT2 promotes HIV-1 latency by preventing nucleolar exit and phase separation of Tat into the Super Elongation Complex

Author

Listed:
  • Jiaxing Jin

    (Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University)

  • Hui Bai

    (Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University)

  • Han Yan

    (Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University)

  • Ting Deng

    (Tianjin Medical University Cancer Institute and Hospital)

  • Tianyu Li

    (Wuhan University)

  • Ruijing Xiao

    (Wuhan University)

  • Lina Fan

    (Nankai University)

  • Xue Bai

    (Tianjin Medical University)

  • Hanhan Ning

    (Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University)

  • Zhe Liu

    (Tianjin Medical University)

  • Kai Zhang

    (Tianjin Medical University)

  • Xudong Wu

    (Tianjin Medical University)

  • Kaiwei Liang

    (Wuhan University)

  • Ping Ma

    (Nankai University)

  • Xin Gao

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Tianjin Institutes of Health Science)

  • Deqing Hu

    (Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University)

Abstract

The HIV-1 Tat protein hijacks the Super Elongation Complex (SEC) to stimulate viral transcription and replication. However, the mechanisms underlying Tat activation and inactivation, which mediate HIV-1 productive and latent infection, respectively, remain incompletely understood. Here, through a targeted complementary DNA (cDNA) expression screening, we identify PRMT2 as a key suppressor of Tat activation, thus contributing to proviral latency in multiple cell line latency models and in HIV-1-infected patient CD4+ T cells. Our data reveal that the transcriptional activity of Tat is oppositely regulated by NPM1-mediated nucleolar retention and AFF4-induced phase separation in the nucleoplasm. PRMT2 preferentially methylates Tat arginine 52 (R52) to reinforce its nucleolar sequestration while simultaneously counteracting its incorporation into the SEC droplets, thereby leading to its functional inactivation to promote proviral latency. Thus, our studies unveil a central and unappreciated role for Tat methylation by PRMT2 in connecting its subnuclear distribution, liquid droplet formation, and transactivating function, which could be therapeutically targeted to eradicate latent viral reservoirs.

Suggested Citation

  • Jiaxing Jin & Hui Bai & Han Yan & Ting Deng & Tianyu Li & Ruijing Xiao & Lina Fan & Xue Bai & Hanhan Ning & Zhe Liu & Kai Zhang & Xudong Wu & Kaiwei Liang & Ping Ma & Xin Gao & Deqing Hu, 2023. "PRMT2 promotes HIV-1 latency by preventing nucleolar exit and phase separation of Tat into the Super Elongation Complex," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43060-1
    DOI: 10.1038/s41467-023-43060-1
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    References listed on IDEAS

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    1. Feng Dong & Qian Li & Chao Yang & Dawei Huo & Xing Wang & Chunbo Ai & Yu Kong & Xiaoyu Sun & Wen Wang & Yan Zhou & Xing Liu & Wei Li & Weiwei Gao & Wen Liu & Chunsheng Kang & Xudong Wu, 2018. "PRMT2 links histone H3R8 asymmetric dimethylation to oncogenic activation and tumorigenesis of glioblastoma," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    2. Huasong Lu & Dan Yu & Anders S. Hansen & Sourav Ganguly & Rongdiao Liu & Alec Heckert & Xavier Darzacq & Qiang Zhou, 2018. "Phase-separation mechanism for C-terminal hyperphosphorylation of RNA polymerase II," Nature, Nature, vol. 558(7709), pages 318-323, June.
    3. Liling Wan & Shasha Chong & Fan Xuan & Angela Liang & Xiaodong Cui & Leah Gates & Thomas S. Carroll & Yuanyuan Li & Lijuan Feng & Guochao Chen & Shu-Ping Wang & Michael V. Ortiz & Sara K. Daley & Xiao, 2020. "Impaired cell fate through gain-of-function mutations in a chromatin reader," Nature, Nature, vol. 577(7788), pages 121-126, January.
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