Nicotinamide phosphoribosyltransferase/sirtuin 1 pathway is involved in human immunodeficiency virus type 1 Tat-mediated long terminal repeat transactivation.
Tat is a multifunctional transactivator encoded by human immunodeficiency virus type 1 (HIV-1). Tat transactivating activity is controlled by nicotinamide adenine nucleotide(+) (NAD(+))-dependent deacetylase sirtuin 1 (SIRT1). Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme in the conversion of nicotinamide into NAD(+), which is crucial for SIRT1 activation. Thus, the effect of Nampt on Tat-regulated SIRT activity was studied in Hela-CD4-beta-gal (MAGI) cells. We demonstrated that Tat caused NAD(+) depletion and inhibited Nampt mRNA and protein expression in MAGI cells. Resveratrol reversed Tat-induced NAD(+) depletion and inhibition of Nampt mRNA and protein expression. Further investigation revealed that Tat-induced inhibition of SIRT1 activity was potentiated in Nampt-knockdown by Nampt siRNA compared to treatment with Tat alone. Nampt siRNA potentiated Tat-induced HIV-1 transactivation in MAGI cells. Altogether, these results indicate that Nampt is critical in the regulation of Tat-induced inhibition of SIRT1 activity and long terminal repeat (LTR) transactivation. Nampt/SIRT1 pathway could be a novel therapeutic tool for the treatment of HIV-1 infection.
Zhang
Hong-Sheng
HS
College of Life Science & Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing 100124, China. zhanghs@bjut.edu.cn
Sang
Wei-Wei
WW
Wang
Yu-Ou
YO
Liu
Wei
W
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D009243:NAD / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D015533:Transcriptional Activation; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D015704:CD4 Antigens; D013267:Stilbenes; D054322:tat Gene Products, Human Immunodeficiency Virus; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; D001616:beta-Galactosidase; D056564:Sirtuin 1; D000077185:Resveratrol