TRIM28 promotes HIV-1 latency by SUMOylating CDK9 and inhibiting P-TEFb.

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.
Mesh Terms:
Cell Line, Tumor, Cyclin-Dependent Kinase 9, Gene Expression Regulation, Viral, HEK293 Cells, HIV Infections, HIV-1, HeLa Cells, Host-Pathogen Interactions, Humans, Positive Transcriptional Elongation Factor B, RNA Interference, Sumoylation, Tripartite Motif-Containing Protein 28, Virus Latency, Virus Replication
Elife
Date: Dec. 17, 2018
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