FKBP3 Induces Human Immunodeficiency Virus Type 1 Latency by Recruiting Histone Deacetylase 1/2 to the Viral Long Terminal Repeat

Xinyi Yang; Xiaying Zhao; Yuqi Zhu; Yinzhong Shen; Yanan Wang; Panpan Lu; Zhengtao Jiang; Hanyu Pan; Jinlong Yang; Jingna Xun; Lin Zhao; Jing Wang; Zhiming Liang; Xiaoting Shen; Yue Liang; Qinru Lin; Huitong Liang; Lu Jin; Dengji Zhang; Jun Liu; Bin Wang; Shibo Jiang; Jianqing Xu; Hao Wu; Hongzhou Lu; Huanzhang Zhu

doi:10.1128/mBio.00795-21

mBio (Aug 2021)

FKBP3 Induces Human Immunodeficiency Virus Type 1 Latency by Recruiting Histone Deacetylase 1/2 to the Viral Long Terminal Repeat

Xinyi Yang,
Xiaying Zhao,
Yuqi Zhu,
Yinzhong Shen,
Yanan Wang,
Panpan Lu,
Zhengtao Jiang,
Hanyu Pan,
Jinlong Yang,
Jingna Xun,
Lin Zhao,
Jing Wang,
Zhiming Liang,
Xiaoting Shen,
Yue Liang,
Qinru Lin,
Huitong Liang,
Lu Jin,
Dengji Zhang,
Jun Liu,
Bin Wang,
Shibo Jiang,
Jianqing Xu,
Hao Wu,
Hongzhou Lu,
Huanzhang Zhu

Affiliations

Xinyi Yang: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Xiaying Zhao: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Yuqi Zhu: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Yinzhong Shen: Department of Infectious Disease, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Yanan Wang: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Panpan Lu: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Zhengtao Jiang: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Hanyu Pan: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Jinlong Yang: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Jingna Xun: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Lin Zhao: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Jing Wang: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Zhiming Liang: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Xiaoting Shen: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Yue Liang: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Qinru Lin: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Huitong Liang: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Lu Jin: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Dengji Zhang: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Jun Liu: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Bin Wang: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China
Shibo Jiang: Department of Infectious Disease, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Jianqing Xu: Department of Infectious Disease, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Hao Wu: Center for Infectious Diseases, Beijing You'an Hospital, Capital Medical University, Fengtai District, Beijing, China
Hongzhou Lu: Department of Infectious Disease, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
Huanzhang Zhu: State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China

DOI: https://doi.org/10.1128/mBio.00795-21
Journal volume & issue: Vol. 12, no. 4

Abstract

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ABSTRACT Human immunodeficiency virus type 1 (HIV-1) cannot be completely eliminated because of existence of the latent HIV-1 reservoir. However, the facts of HIV-1 latency, including its establishment and maintenance, are incomplete. FKBP3, encoded by the FKBP3 gene, belongs to the immunophilin family of proteins and is involved in immunoregulation and such cellular processes as protein folding. In a previous study, we found that FKBP3 may be related to HIV-1 latency using CRISPR screening. In this study, we knocked out the FKBP3 gene in multiple latently infected cell lines to promote latent HIV-1 activation. We found that FKBP3 could indirectly bind to the HIV-1 long terminal repeat through interaction with YY1, thereby recruiting histone deacetylase 1/2 to it. This promotes histone deacetylation and induces HIV-1 latency. Finally, in a primary latent cell model, we confirmed the effect of FKBP3 knockout on the latent activation of HIV-1. Our results suggest a new mechanism for the epigenetic regulation of HIV-1 latency and a new potential target for activating latent HIV-1. IMPORTANCE The primary reason why AIDS cannot be completely cured is the existence of a latent HIV-1 reservoir. Currently, the facts of HIV-1 latency, including its establishment and maintenance, are incomplete. Using a CRISPR library in our earlier screening of genes related to HIV-1 latency, we identified FBKP3 as a candidate gene related to HIV-1 latency. Therefore, in this mechanistic study, we first confirmed the HIV-1 latency-promoting effect of FKBP3 and determined that FKBP3 promotes histone deacetylation by recruiting histone deacetylase 1/2 to the HIV-1 long terminal repeat. We also confirmed, for the first time, that FKBP3 can act as a transcription factor (TF) recruitment scaffold and participate in epigenetic regulation of HIV-1 latency. These findings suggest a new mechanism for the epigenetic regulation of HIV-1 latency and a new potential target for activating latent HIV-1.

Published in mBio

ISSN: 2161-2129 (Print); 2150-7511 (Online)
Publisher: American Society for Microbiology
Country of publisher: United States
LCC subjects: Science: Microbiology
Website: https://journals.asm.org/journal/mbio

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