UHRF1 Suppresses HIV-1 Transcription and Promotes HIV-1 Latency by Competing with p-TEFb for Ubiquitination-Proteasomal Degradation of Tat
ABSTRACT HIV-1 remains incurable due to viral reservoirs, which lead to durably latent HIV infection. Identifying novel host factors and deciphering the molecular mechanisms involved in the establishment and maintenance of latency are critical to discover new targets for the development of novel ant...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2021-08-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01625-21 |
| _version_ | 1819013084570714112 |
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| author | Taizhen Liang Qiao Zhang Ziyao Wu Pei Chen Yifan Huang Shuwen Liu Lin Li |
| author_facet | Taizhen Liang Qiao Zhang Ziyao Wu Pei Chen Yifan Huang Shuwen Liu Lin Li |
| author_sort | Taizhen Liang |
| collection | DOAJ |
| description | ABSTRACT HIV-1 remains incurable due to viral reservoirs, which lead to durably latent HIV infection. Identifying novel host factors and deciphering the molecular mechanisms involved in the establishment and maintenance of latency are critical to discover new targets for the development of novel anti-HIV agents. Here, we show that ubiquitin-like with PHD and RING finger domain 1 (UHRF1) modulates HIV-1 5′-long terminal repeat (LTR)-driven transcription of the viral genome as a novel HIV-1 restriction factor. Correspondingly, UHRF1 depletion reversed the latency of HIV-1 proviruses. Mechanistically, UHRF1 competed with positive transcription factor b (p-TEFb) for the binding to the cysteine-rich motifs of HIV-1 Tat via its TTD, PHD, and RING finger domains. Furthermore, UHRF1 mediated K48-linked ubiquitination and proteasomal degradation of Tat in RING-dependent ways, leading to the disruption of Tat/cyclin T1/CDK9 complex and consequential impediment of transcription elongation. In summary, our findings revealed that UHRF1 is an important mediator of HIV-1 latency by controlling Tat-mediated transcriptional activation, providing novel insights on host-pathogen interaction for modulating HIV-1 latency, beneficial for the development of anti-AIDS therapies. IMPORTANCE HIV-1 latency is systematically modulated by host factors and viral proteins. In our work, we identified a critical role of host factor ubiquitin-like with PHD and RING finger domain 1 (UHRF1) in HIV-1 latency via the modulation of the viral protein Tat stability. By disrupting the Tat/cyclin T1/CDK9 complex, UHRF1 promotes the suppression of HIV-1 transcription and maintenance of HIV-1 latency. Our findings provide novel insights in controlling Tat expression via host-pathogen interaction for modulating HIV-1 latency. Based on our results, modulating UHRF1 expression or activity by specific inhibitors is a potential therapeutic strategy for latency reversal in HIV-1 patients. |
| first_indexed | 2024-12-21T01:54:19Z |
| format | Article |
| id | doaj.art-06181b3a52d14e46ba208ebaa845b1f1 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-21T01:54:19Z |
| publishDate | 2021-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-06181b3a52d14e46ba208ebaa845b1f12022-12-21T19:19:49ZengAmerican Society for MicrobiologymBio2150-75112021-08-0112410.1128/mBio.01625-21UHRF1 Suppresses HIV-1 Transcription and Promotes HIV-1 Latency by Competing with p-TEFb for Ubiquitination-Proteasomal Degradation of TatTaizhen Liang0Qiao Zhang1Ziyao Wu2Pei Chen3Yifan Huang4Shuwen Liu5Lin Li6Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaSchool of Medicine, Jinan University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, ChinaABSTRACT HIV-1 remains incurable due to viral reservoirs, which lead to durably latent HIV infection. Identifying novel host factors and deciphering the molecular mechanisms involved in the establishment and maintenance of latency are critical to discover new targets for the development of novel anti-HIV agents. Here, we show that ubiquitin-like with PHD and RING finger domain 1 (UHRF1) modulates HIV-1 5′-long terminal repeat (LTR)-driven transcription of the viral genome as a novel HIV-1 restriction factor. Correspondingly, UHRF1 depletion reversed the latency of HIV-1 proviruses. Mechanistically, UHRF1 competed with positive transcription factor b (p-TEFb) for the binding to the cysteine-rich motifs of HIV-1 Tat via its TTD, PHD, and RING finger domains. Furthermore, UHRF1 mediated K48-linked ubiquitination and proteasomal degradation of Tat in RING-dependent ways, leading to the disruption of Tat/cyclin T1/CDK9 complex and consequential impediment of transcription elongation. In summary, our findings revealed that UHRF1 is an important mediator of HIV-1 latency by controlling Tat-mediated transcriptional activation, providing novel insights on host-pathogen interaction for modulating HIV-1 latency, beneficial for the development of anti-AIDS therapies. IMPORTANCE HIV-1 latency is systematically modulated by host factors and viral proteins. In our work, we identified a critical role of host factor ubiquitin-like with PHD and RING finger domain 1 (UHRF1) in HIV-1 latency via the modulation of the viral protein Tat stability. By disrupting the Tat/cyclin T1/CDK9 complex, UHRF1 promotes the suppression of HIV-1 transcription and maintenance of HIV-1 latency. Our findings provide novel insights in controlling Tat expression via host-pathogen interaction for modulating HIV-1 latency. Based on our results, modulating UHRF1 expression or activity by specific inhibitors is a potential therapeutic strategy for latency reversal in HIV-1 patients.https://journals.asm.org/doi/10.1128/mBio.01625-21HIV-1 latencyUHRF1Tatp-TEFbRING finger |
| spellingShingle | Taizhen Liang Qiao Zhang Ziyao Wu Pei Chen Yifan Huang Shuwen Liu Lin Li UHRF1 Suppresses HIV-1 Transcription and Promotes HIV-1 Latency by Competing with p-TEFb for Ubiquitination-Proteasomal Degradation of Tat mBio HIV-1 latency UHRF1 Tat p-TEFb RING finger |
| title | UHRF1 Suppresses HIV-1 Transcription and Promotes HIV-1 Latency by Competing with p-TEFb for Ubiquitination-Proteasomal Degradation of Tat |
| title_full | UHRF1 Suppresses HIV-1 Transcription and Promotes HIV-1 Latency by Competing with p-TEFb for Ubiquitination-Proteasomal Degradation of Tat |
| title_fullStr | UHRF1 Suppresses HIV-1 Transcription and Promotes HIV-1 Latency by Competing with p-TEFb for Ubiquitination-Proteasomal Degradation of Tat |
| title_full_unstemmed | UHRF1 Suppresses HIV-1 Transcription and Promotes HIV-1 Latency by Competing with p-TEFb for Ubiquitination-Proteasomal Degradation of Tat |
| title_short | UHRF1 Suppresses HIV-1 Transcription and Promotes HIV-1 Latency by Competing with p-TEFb for Ubiquitination-Proteasomal Degradation of Tat |
| title_sort | uhrf1 suppresses hiv 1 transcription and promotes hiv 1 latency by competing with p tefb for ubiquitination proteasomal degradation of tat |
| topic | HIV-1 latency UHRF1 Tat p-TEFb RING finger |
| url | https://journals.asm.org/doi/10.1128/mBio.01625-21 |
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