TRIM28 promotes HIV-1 latency by SUMOylating CDK9 and inhibiting P-TEFb.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30652970.
- Also identified by DOI 10.7554/eLife.42426 and PMC identifier 6361614.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Cyclin-Dependent Kinase 9
- HIV Infections
- HIV-1
- Positive Transcriptional Elongation Factor B
- Tripartite Motif-Containing Protein 28
- Virus Latency