SIRT1 regulates Tat-induced HIV-1 transactivation through activating AMP-activated protein kinase.
Transcription of human immunodeficiency virus (HIV-1) is activated by viral Tat protein which regulates HIV-long terminal repeat (LTR) transcription and elongation. HIV-1 Tat protein is a substrate for the deacetylase activity of sirtuin 1 (SIRT1). Here we investigate the signaling pathway involved in Tat-induced HIV-1 transactivation through SIRT1. Western blot analysis showed a significant reduction in AMPK activation and downstream acetyl-CoA carboxylase (ACC) activation in response to Tat treatment. NAD(+) levels and SIRT1 activity were also decreased with Tat treatment. SIRT1 activator resveratrol reversed Tat-mediated reduction in AMPK activation and downstream ACC activation; while SIRT1 inhibitor nicotinamide or knockdown of SIRT1 by siRNA potentiated Tat-mediated reduction in AMPK activation and downstream ACC activation. Consistent with this association, AMPK activator AICAR as well as resveratrol inhibited Tat-induced HIV-1 transactivation. On the contrary, AMPK inhibitor compound C, knockdown of AMPK by siRNA as well as nicotinamide or knockdown of SIRT1 by siRNA potentiated Tat-induced HIV-1 transactivation. Collectively, our data provide new insights into understanding of the molecular mechanisms of Tat-regulated transcription, suggesting that targeting SIRT1-AMPK pathway could serve as a new target for the development of new anti HIV-1 agents.
Zhang
Hong-Sheng
HS
Department of Virology & Pharmacology, College of Life Science & Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing 100124, China. zhanghs@bjut.edu.cn
Wu
Meng-Ran
MR
D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral; D055785:Gene Knockdown Techniques; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D015533:Transcriptional Activation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D013267:Stilbenes; D054322:tat Gene Products, Human Immunodeficiency Virus; D009243:NAD; D009536:Niacinamide; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D000103:Acetyl-CoA Carboxylase; D000077185:Resveratrol