PRMT3 reverses HIV-1 latency by increasing chromatin accessibility to form a TEAD4-P-TEFb-containing transcriptional hub

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-05-15 DOI:10.1038/s41467-025-59578-5

Xinyu Wang, Yuhua Xue, Lin Li, Jinwen Song, Lei Jia, Xu Li, Miao Fan, Lu Lu, Wen Su, Jingwan Han, Dandan Lin, Rongdiao Liu, Xiang Gao, Yafei Guo, Zixun Xiang, Chunjing Chen, Linyu Wan, Huihui Chong, Yuxian He, Fusheng Wang, Kaihu Yao, Qiang Zhou, Dan Yu

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Abstract

Latent HIV-1 presents a formidable challenge for viral eradication. HIV-1 transcription and latency reversal require interactions between the viral promoter and host proteins. Here, we perform the dCas9-targeted locus-specific protein analysis and discover the interaction of human arginine methyltransferase 3 (PRMT3) with the HIV-1 promoter. This interaction reverses latency in cell line models and primary cells from latently infected persons by increasing the levels of H4R3Me2a and transcription factor P-TEFb at the viral promoter. PRMT3 is found to promote chromatin accessibility and transcription of HIV-1 and a small subset of host genes in regions harboring the classical recognition motif for another transcription factor TEAD4. This motif attracts TEAD4 and PRMT3 to the viral promoter to synergistically activate transcription. Physical interactions among PRMT3, P-TEFb, and TEAD4 exist, which may help form a transcriptional hub at the viral promoter. Our study reveals the potential of targeting these hub proteins to eradicate latent HIV-1.

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PRMT3通过增加染色质可及性来逆转HIV-1潜伏期，形成含有tead4 - p - tefb的转录中心

潜伏的HIV-1对病毒根除提出了一个巨大的挑战。HIV-1的转录和潜伏期逆转需要病毒启动子和宿主蛋白之间的相互作用。在这里，我们进行了dcas9靶向的位点特异性蛋白分析，并发现了人类精氨酸甲基转移酶3 （PRMT3）与HIV-1启动子的相互作用。这种相互作用通过增加病毒启动子上的H4R3Me2a和转录因子P-TEFb的水平，逆转了潜伏感染者的细胞系模型和原代细胞中的潜伏期。研究发现，PRMT3可以促进HIV-1和一小部分宿主基因的染色质可及性和转录，这些基因位于另一个转录因子TEAD4的经典识别基序区域。该基序将TEAD4和PRMT3吸引到病毒启动子上，协同激活转录。PRMT3、P-TEFb和TEAD4之间存在物理相互作用，这可能有助于在病毒启动子上形成转录中心。我们的研究揭示了靶向这些中心蛋白根除潜伏的HIV-1的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.