Int J Biol Sci 2014; 10(10):1138-1149. doi:10.7150/ijbs.10366
Interaction between HIV-1 Tat and DNA-PKcs modulates HIV transcription and class switch recombination
1. Department of Radiation Toxicology and Oncology; Beijing Institute of Radiation Medicine, 100850, Beijing, China;
2. The State Key Laboratory of NBC Protection for Civilian, 102205, Beijing, China;
3. Beijing Institute of Health Administration and Medical Information, 100850, Beijing, China;
4. Shandong Provincial Key Laboratory of Plastic and Microscopic Repair Technology, Institute of Plastic Surgery, Weifang Medical University, 261053, Weifang, Shandong Province, China.
# These authors contributed equally to this work.
HIV-1 tat targets a variety of host cell proteins to facilitate viral transcription and disrupts host cellular immunity by inducing lymphocyte apoptosis, but whether it influences humoral immunity remains unclear. Previously, our group demonstrated that tat depresses expression of DNA-PKcs, a critical component of the non-homologous end joining pathway (NHEJ) of DNA double-strand breaks repair, immunoglobulin class switch recombination (CSR) and V(D)J recombination, and sensitizes cells to ionizing radiation. In this study, we demonstrated that HIV-1 Tat down-regulates DNA-PKcs expression by directly binding to the core promoter sequence. In addition, Tat interacts with and activates the kinase activity of DNA-PKcs in a dose-dependent and DNA independent manner. Furthermore, Tat inhibits class switch recombination (CSR) at low concentrations (≤4 µg/ml) and stimulates CSR at high concentrations (≥8 µg/ml). On the other hand, low protein level and high kinase activity of DNA-PKcs promotes HIV-1 transcription, while high protein level and low kinase activity inhibit HIV-1 transcription. Co-immunoprecipitation results revealed that DNA-PKcs forms a large complex comprised of Cyclin T1, CDK9 and Tat via direct interacting with CDK9 and Tat but not Cyclin T1. Taken together, our results provide new clues that Tat regulates host humoral immunity via both transcriptional depression and kinase activation of DNA-PKcs. We also raise the possibility that inhibitors and interventions directed towards DNA-PKcs may inhibit HIV-1 transcription in AIDS patients.
Keywords: HIV-1 tat, DNA-PKcs
Zhang SM, Zhang H, Yang TY, Ying TY, Yang PX, Liu XD, Tang SJ, Zhou PK. Interaction between HIV-1 Tat and DNA-PKcs modulates HIV transcription and class switch recombination. Int J Biol Sci 2014; 10(10):1138-1149. doi:10.7150/ijbs.10366. Available from http://www.ijbs.com/v10p1138.htm