FBXO34 promotes latent HIV-1 activation by post-transcriptional modulation

作者：Xinyi Yang, Xiaying Zhao, Yuqi Zhu, Jingna Xun, Wen Qin, Hanyu Pan, Jin‐Long Yang, Jing Wang, Zhimin Liang, Xiaoting Shen, Liang Yue, Qinru Lin, Huitong Liang, Min Li, Jun Chen, Shibo Jiang, Jianqing Xu, Hongzhou Lu, Huanzhang Zhu · 发表于：Emerging Microbes & Infections · 年份：2022 · DOI：10.1080/22221751.2022.2140605 · 被引用次数：10 · 研究领域：HIV Research and Treatment、CRISPR and Genetic Engineering、HIV/AIDS drug development and treatment

Acquired immunodeficiency syndrome (AIDS) cannot be completely cured, mainly due to the existence of a latent HIV-1 reservoir. However, our current understanding of the molecular mechanisms underlying the establishment and maintenance of HIV-1 latent reservoir is not comprehensive. Here, using a genome-wide CRISPR-Cas9 activation library screening, we identified E3 ubiquitin ligase F-box protein 34 (FBXO34) and the substrate of FBXO34, heterogeneous nuclear ribonucleoprotein U (hnRNP U) was identified by affinity purification mass spectrometry, as new host factors related to HIV-1 latent maintenance. Overexpression of FBXO34 or knockout of hnRNP U can activate latent HIV-1 in multiple latent cell lines. FBXO34 mainly promotes hnRNP U ubiquitination, which leads to hnRNP U degradation and abolishment of the interaction between hnRNP U and HIV-1 mRNA. In a latently infected cell line, hnRNP U interacts with the ReV region of HIV-1 mRNA through amino acids 1-339 to hinder HIV-1 translation, thereby, promoting HIV-1 latency. Importantly, we confirmed the role of the FBXO34/hnRNP U axis in the primary CD4+ T lymphocyte model, and detected differences in hnRNP U expression levels in samples from patients treated with antiretroviral therapy (ART) and healthy people, which further suggests that the FBXO34/hnRNP U axis is a new pathway involved in HIV-1 latency. These results provide mechanistic insights into the critical role of ubiquitination and hnRNP U in HIV-1 latency. This novel...