TRIM28 Promotes HIV-1 Latency by SUMOylating CDK9 and Inhibiting P-TEFb

Elife. 2019 Jan 17;8:e42426. doi: 10.7554/eLife.42426.

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.

Keywords: HIV-1 Latency; P-TEFb; SUMOylation; TRIM28; human; infectious disease; latency-reversing agents; microbiology; promoter-proximal pausing; virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 9 / genetics*
  • Cyclin-Dependent Kinase 9 / metabolism
  • Gene Expression Regulation, Viral
  • HEK293 Cells
  • HIV Infections / genetics*
  • HIV Infections / metabolism
  • HIV Infections / virology
  • HIV-1 / genetics*
  • HIV-1 / physiology
  • HeLa Cells
  • Host-Pathogen Interactions / genetics
  • Humans
  • Positive Transcriptional Elongation Factor B / genetics*
  • Positive Transcriptional Elongation Factor B / metabolism
  • RNA Interference
  • Sumoylation
  • Tripartite Motif-Containing Protein 28 / genetics*
  • Tripartite Motif-Containing Protein 28 / metabolism
  • Virus Latency / genetics*
  • Virus Replication / genetics

Substances

  • Tripartite Motif-Containing Protein 28
  • Positive Transcriptional Elongation Factor B
  • CDK9 protein, human
  • Cyclin-Dependent Kinase 9