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

Authors :
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
Source :
Nature Communications, Vol 14, Iss 1, Pp 1-18 (2023)
Publication Year :
2023
Publisher :
Nature Portfolio, 2023.

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.

Subjects

Subjects :
Science

Details

Language :
English
ISSN :
20411723
Volume :
14
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Nature Communications
Publication Type :
Academic Journal
Accession number :
edsdoj.47ff490a35ef49b9882d927b501c3988
Document Type :
article
Full Text :
https://doi.org/10.1038/s41467-023-43060-1