CDK13, a New Potential Human Immunodeficiency Virus Type 1 Inhibitory Factor Regulating Viral mRNA Splicing
- 15 July 2008
- journal article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 82 (14), 7155-7166
- https://doi.org/10.1128/jvi.02543-07
Abstract
The human immunodeficiency virus type 1 (HIV-1) Tat is a 14-kDa viral protein that acts as a potent transactivator by binding to the transactivation-responsive region, a structured RNA element located at the 5′ end of all HIV-1 transcripts. Tat transactivates viral gene expression by inducing the phosphorylation of the C-terminal domain of RNA polymerase II through several Tat-activated kinases and by recruiting chromatin-remodeling complexes and histone-modifying enzymes to the HIV-1 long terminal repeat. Histone acetyltransferases, including p300 and hGCN5, not only acetylate histones but also acetylate Tat at lysine positions 50 and 51 in the arginine-rich motif. Acetylated Tat at positions 50 and 51 interacts with a specialized protein module, the bromodomain, and recruits novel factors having this particular domain, such as P/CAF and SWI/SNF. In addition to having its effect on transcription, Tat has been shown to be involved in splicing. In this study, we demonstrate that Tat interacts with cyclin-dependent kinase 13 (CDK13) both in vivo and in vitro. We also found that CDK13 increases HIV-1 mRNA splicing and favors the production of the doubly spliced protein Nef. In addition, we demonstrate that CDK13 acts as a possible restriction factor, in that its overexpression decreases the production of the viral proteins Gag and Env and subsequently suppresses virus production. Using small interfering RNA against CDK13, we show that silencing of CDK13 leads to a significant increase in virus production. Finally, we demonstrate that CDK13 mediates its effect on splicing through the phosphorylation of ASF/SF2.Keywords
This publication has 59 references indexed in Scilit:
- The Ebola Virus VP35 Protein Is a Suppressor of RNA SilencingPLoS Pathogens, 2007
- CDK13/CDC2L5 interacts with L-type cyclins and regulates alternative splicingBiochemical and Biophysical Research Communications, 2007
- Identification and Characterization of the CDK12/Cyclin L1 Complex Involved in Alternative Splicing RegulationMolecular and Cellular Biology, 2006
- Human Immunodeficiency Virus Type 2 Gag Interacts Specifically with PRP4, a Serine-Threonine Kinase, and Inhibits Phosphorylation of Splicing Factor SF2Journal of Virology, 2004
- CDK11 Complexes Promote Pre-mRNA SplicingPublished by Elsevier BV ,2003
- HIV-1 Tat transcriptional activity is regulated by acetylationThe EMBO Journal, 1999
- cdc2 Kinase-Mediated Phosphorylation of Splicing Factor SF2/ASFBiochemical and Biophysical Research Communications, 1998
- Novel SR-Protein-Specific Kinase, SRPK2, Disassembles Nuclear SpecklesBiochemical and Biophysical Research Communications, 1998
- A serine kinase regulates intracellular localization of splicing factors in the cell cycleNature, 1994
- Identification of two novel human immunodeficiency virus type 1 splice acceptor sites in infected T cell linesJournal of General Virology, 1992