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

• Published in: Nature communications 2023-11, Vol.14 (1), p.7274-7274, Article 7274
• Main Authors: Jin, Jiaxing, Bai, Hui, Yan, Han, Deng, Ting, Li, Tianyu, Xiao, Ruijing, Fan, Lina, Bai, Xue, Ning, Hanhan, Liu, Zhe, Zhang, Kai, Wu, Xudong, Liang, Kaiwei, Ma, Ping, Gao, Xin, Hu, Deqing
• Format: Article
• Language: English
• Subjects: 13/106; 38/15; 38/89; 631/326/596/2556; 631/326/596/2564; 631/337/458/1648; Blood diseases; Cancer; CD4 antigen; Cell culture; Collaboration; Deactivation; Disease prevention; Droplets; Elongation; Epigenetics; Gene expression; Hematology; HIV; Hospitals; Human immunodeficiency virus; Humanities and Social Sciences; Inactivation; Infectious diseases; Kinases; Laboratories; Latency; Latent infection; Localization; Lymphocytes; Lymphocytes T; multidisciplinary; Nucleoli; Phase separation; Proteins; Replication; Research centers; RNA polymerase; Science; Science (multidisciplinary); Tat protein; Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-43060-1

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. The mechanisms regulating Tat function for HIV-1 replication remain poorly understood. Here, the authors reveal that the transcriptional activity of Tat is modulated by a PRMT2-licensed switch between its nucleolar sequestration and phase separation into the nucleoplasmic Super Elongation Complex (SEC) droplets.