PRMT2 promotes HIV-1 latency by preventing nucleolar exit and phase separation of Tat into the Super Elongation Complex.
Jiaxing JinHui BaiHan YanTing DengTianyu LiRuijing XiaoLina FanXue BaiHanhan NingZhe LiuKai ZhangXudong WuKai-Wei LiangPing MaXin GaoDeqing HuPublished in: Nature communications (2023)
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.
Keyphrases
- hiv infected
- antiretroviral therapy
- hiv positive
- human immunodeficiency virus
- hiv testing
- hepatitis c virus
- hiv aids
- men who have sex with men
- sars cov
- transcription factor
- cancer therapy
- nitric oxide
- gene expression
- dna methylation
- high throughput
- high glucose
- endothelial cells
- circulating tumor
- small molecule
- single molecule
- deep learning
- ionic liquid
- machine learning
- protein protein
- drug delivery