FBXO34 promotes latent HIV-1 activation by post-transcriptional modulation. Issue 1 (31st December 2022)

• Record Type: Journal Article
• Authors: Yang, Xinyi; Zhao, Xiaying; Zhu, Yuqi; Xun, Jingna; Wen, Qin; Pan, Hanyu; Yang, Jinlong; Wang, Jing; Liang, Zhimin; Shen, Xiaoting; Liang, Yue; Lin, Qinru; Liang, Huitong; Li, Min; Chen, Jun; Jiang, Shibo; Xu, Jianqing; Lu, Hongzhou; Zhu, Huanzhang
• Is Part Of: Emerging microbes & infections. Volume 11:Issue 1(2022)
• Page Start: 2785
• Page End: 2799
• Publication Date: 2022-12-31
• Subjects: HIV-1 -- Virus latency -- FBXO34 -- hnNRP U -- CRISPR; Medical microbiology -- Periodicals; Communicable diseases -- Periodicals; Infection -- Periodicals; 616.9041
• DOI: 10.1080/22221751.2022.2140605
• Languages: English
• ISSNs: 2222-1751

Abstract

ABSTRACT : 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 FBXO34/hnRNP U axis in HIV transcription may be directly targeted to control HIV reservoirs in patients in the future.