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

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 () and Deqing Hu ()
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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
Deqing Hu: Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43060-1

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