TRIM28 promotes HIV-1 latency by SUMOylating CDK9 and inhibiting P-TEFb
- Sun Yat-sen University, China
- Shenyang Medical College, China
- Sun Yat-Sen University Cancer Center, China
- Guangzhou 8th People's Hospital, China
Abstract
Comprehensively elucidating the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) latency is a priority to achieve a functional cure. As current 'shock' agents failed to efficiently reactivate the latent reservoir, it is important to discover new targets for developing more efficient latency-reversing agents (LRAs). Here we found that TRIM28 potently suppresses HIV-1 expression by utilizing both SUMO E3 ligase activity and epigenetic adaptor function. Through global site-specific SUMO-MS study and serial SUMOylation assays, we identified that P-TEFb catalytic subunit CDK9 is significantly SUMOylated by TRIM28 with SUMO4. The Lys44, Lys56 and Lys68 residues on CDK9 are SUMOylated by TRIM28, which inhibits CDK9 kinase activity or prevents P-TEFb assembly by directly blocking the interaction between CDK9 and Cyclin T1, subsequently inhibits viral transcription and contributes to HIV-1 latency. The manipulation of TRIM28 and its consequent SUMOylation pathway could be the target for developing LRAs.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
National Special Research Program of China for Important Infectious Diseases (2017ZX10202102)
- Hui Zhang
Important Key Program of Natural Science Foundation of China (81730060)
- Hui Zhang
International Collaboration Program of Natural Science Foundation of China and US NIH (81561128007)
- Hui Zhang
Joint-innovation Program in Healthcare for Special Scientific Research Projects of Guangzhou (201803040002)
- Hui Zhang
National Special Research Program of China for Important Infectious Diseases (2018ZX10302103)
- Hui Zhang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Chronically HIV-1-infected participants sampled by this study were recruited from Department of Infectious Diseases in Guangzhou 8th People's Hospital, Guangzhou. The Ethics Review Board of Sun Yat-Sen University and the Ethics Review Board of Guangzhou 8th People's Hospital approved this study. All the participants were given written informed consent with approval of the Ethics Committees. The enrollment of HIV-1-infected individuals was based on the criteria of prolonged suppression of plasma HIV-1 viremia on cART, which is undetectable plasma HIV-1 RNA levels (less than 50 copies/ml) for a minimum of six months, and having high CD4+ T cell count (at least 350 cells/mm3). Blood samples from healthy individuals were obtained from Guangzhou Blood Center. We did not have any interaction with the healthy individuals or protected information, and therefore no informed consent was required. The statement was also included in the Materials and Methods section.
Copyright
© 2019, Ma et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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TRIM28 promotes HIV-1 latency by SUMOylating CDK9 and inhibiting P-TEFb
eLife 8:e42426.
https://doi.org/10.7554/eLife.42426
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