RYBP promotes HIV-1 latency through promoting H2AK119ub and decreasing H3K4me3
Abstract Background Acquired immunodeficiency syndrome (AIDS) cannot be completely cured, and the main obstacle is the existence of viral reservoirs. However, we currently do not fully understand the molecular mechanisms by which HIV-1 latency is established and maintained. Methods Here, based on en...
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BMC
2025-05-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-025-02221-z |
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| author | Xinyi Yang Yuqi Zhu Xiaying Zhao Jingna Xun Xingyu Wang Yipeng Cheng Su Xiong Xingwen Yu Suixiang Li Danqing Wang Zhiliang Hu Yinzhong Shen Shibo Jiang Hongzhou Lu Gang Wang Huanzhang Zhu |
| author_facet | Xinyi Yang Yuqi Zhu Xiaying Zhao Jingna Xun Xingyu Wang Yipeng Cheng Su Xiong Xingwen Yu Suixiang Li Danqing Wang Zhiliang Hu Yinzhong Shen Shibo Jiang Hongzhou Lu Gang Wang Huanzhang Zhu |
| author_sort | Xinyi Yang |
| collection | DOAJ |
| description | Abstract Background Acquired immunodeficiency syndrome (AIDS) cannot be completely cured, and the main obstacle is the existence of viral reservoirs. However, we currently do not fully understand the molecular mechanisms by which HIV-1 latency is established and maintained. Methods Here, based on engineered chromatin immunoprecipitation (enChIP) technology that using FLAG-tagged zinc finger nucleic acid proteins (FLAG-ZFP) that bind to the HIV-1 L region and chromatin immunoprecipitation, we identified RYBP as a new HIV-1 latency-promoting gene. The effect of RYBP on HIV-1 latency was explored in multiple cell lines and primary latency models through gene knockout methods. Western blot and chromatin immunoprecipitation (ChIP) were used to explore the molecular mechanism of RYBP in promoting HIV-1 latency. Results Disruption of RYBP gene can activate latent HIV-1 in different latent cell lines and primary latent cell models. Mechanistically, the HIV-1 long terminal repeats (LTR) region binding protein Yin Yang 1 (YY1) can recruit RYBP to the HIV-1 L region. Then, RYBP can further recruit KDM2B, thereby promoting the increased ubiquitination level of H2AK119 and decreases the level of H3K4me3, to decrease HIV-1 L transcriptional elongation and enter a latent state. At the same time, during the stage of viral transcription and replication, Tat protein can inhibit the expression of RYBP, promoting viral transcription and replication. Finally, we found that the H2AK119ub inhibitor PRT4165 can promote latent HIV-1 activation and has good synergy with reported latent reactivating agents. Conclusion These results provide mechanistically new insights into a critical role of RYBP in the regulation of histone modification and H2AK119ub may be directly targeted to control HIV reservoirs. |
| format | Article |
| id | doaj-art-c7b1fb050bf149a5b1439f4e0a455872 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-c7b1fb050bf149a5b1439f4e0a4558722025-08-20T03:53:58ZengBMCCell Communication and Signaling1478-811X2025-05-0123111510.1186/s12964-025-02221-zRYBP promotes HIV-1 latency through promoting H2AK119ub and decreasing H3K4me3Xinyi Yang0Yuqi Zhu1Xiaying Zhao2Jingna Xun3Xingyu Wang4Yipeng Cheng5Su Xiong6Xingwen Yu7Suixiang Li8Danqing Wang9Zhiliang Hu10Yinzhong Shen11Shibo Jiang12Hongzhou Lu13Gang Wang14Huanzhang Zhu15State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan UniversityState Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan UniversityState Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan UniversityState Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan UniversityState Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan UniversityState Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan UniversityState Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan UniversityState Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan UniversityState Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan UniversityYunnan Provincial Infectious Diseases Hospital/Yunnan AIDS Care CenterDepartment of Infectious Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing Medical University, Center for Global Health, School of Public HealthScientific Research Center, Shanghai Public Health Clinical Center, Fudan UniversityKey Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan UniversityDepartment of Infectious Diseases and Nursing Research Institution, National Clinical Research Center for Infectious Diseases, The Third People’s Hospital of ShenzhenState Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan UniversityState Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan UniversityAbstract Background Acquired immunodeficiency syndrome (AIDS) cannot be completely cured, and the main obstacle is the existence of viral reservoirs. However, we currently do not fully understand the molecular mechanisms by which HIV-1 latency is established and maintained. Methods Here, based on engineered chromatin immunoprecipitation (enChIP) technology that using FLAG-tagged zinc finger nucleic acid proteins (FLAG-ZFP) that bind to the HIV-1 L region and chromatin immunoprecipitation, we identified RYBP as a new HIV-1 latency-promoting gene. The effect of RYBP on HIV-1 latency was explored in multiple cell lines and primary latency models through gene knockout methods. Western blot and chromatin immunoprecipitation (ChIP) were used to explore the molecular mechanism of RYBP in promoting HIV-1 latency. Results Disruption of RYBP gene can activate latent HIV-1 in different latent cell lines and primary latent cell models. Mechanistically, the HIV-1 long terminal repeats (LTR) region binding protein Yin Yang 1 (YY1) can recruit RYBP to the HIV-1 L region. Then, RYBP can further recruit KDM2B, thereby promoting the increased ubiquitination level of H2AK119 and decreases the level of H3K4me3, to decrease HIV-1 L transcriptional elongation and enter a latent state. At the same time, during the stage of viral transcription and replication, Tat protein can inhibit the expression of RYBP, promoting viral transcription and replication. Finally, we found that the H2AK119ub inhibitor PRT4165 can promote latent HIV-1 activation and has good synergy with reported latent reactivating agents. Conclusion These results provide mechanistically new insights into a critical role of RYBP in the regulation of histone modification and H2AK119ub may be directly targeted to control HIV reservoirs.https://doi.org/10.1186/s12964-025-02221-zRYBPKDM2BHIV-1 latencyH2AK119ubEnChIP |
| spellingShingle | Xinyi Yang Yuqi Zhu Xiaying Zhao Jingna Xun Xingyu Wang Yipeng Cheng Su Xiong Xingwen Yu Suixiang Li Danqing Wang Zhiliang Hu Yinzhong Shen Shibo Jiang Hongzhou Lu Gang Wang Huanzhang Zhu RYBP promotes HIV-1 latency through promoting H2AK119ub and decreasing H3K4me3 Cell Communication and Signaling RYBP KDM2B HIV-1 latency H2AK119ub EnChIP |
| title | RYBP promotes HIV-1 latency through promoting H2AK119ub and decreasing H3K4me3 |
| title_full | RYBP promotes HIV-1 latency through promoting H2AK119ub and decreasing H3K4me3 |
| title_fullStr | RYBP promotes HIV-1 latency through promoting H2AK119ub and decreasing H3K4me3 |
| title_full_unstemmed | RYBP promotes HIV-1 latency through promoting H2AK119ub and decreasing H3K4me3 |
| title_short | RYBP promotes HIV-1 latency through promoting H2AK119ub and decreasing H3K4me3 |
| title_sort | rybp promotes hiv 1 latency through promoting h2ak119ub and decreasing h3k4me3 |
| topic | RYBP KDM2B HIV-1 latency H2AK119ub EnChIP |
| url | https://doi.org/10.1186/s12964-025-02221-z |
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