Inhibition of SIRT1 by HIV-1 viral protein Tat results in activation of p53 pathway.
Human immunodeficiency virus-1 (HIV-1) disease is characterized by a relentless decline in CD4(+) T cells, resulting in the development of AIDS. Extracellular Tat secreted from the HIV-1 infected cells, enters non-infected T cells to induce apoptosis. A number of mechanisms, none of which is mutually exclusive, have been attributed to the cell depletion property of Tat protein. In the present communication, we provide evidence that the cell-killing effect of Tat is mediated by the activation of p53 pathway via inhibition of SIRT1, an NAD(+)-dependent deacetylase belonging to class III histone deacetylases. This evidence is based on the following experimental facts reported herein: (1) Overexpression of Tat protein decreases both the deacetylase and promoter activity of SIRT1, (2) SIRT1 inhibition by Tat involves increased levels of acetylated p53 and (3) The activation of p53 leads to subsequent increases in the expression of p53 target genes, p21 and BAX.
Department of Pediatrics Hematology and Oncology, Hannover Medical School, Carl Neuberg Str-1, 30625 Hannover, Germany.
Basant Kumar
BK
Thakur
Angelika
A
Chandra
Tino
T
Dittrich
Karl
K
Welte
Prakash
P
Chandra
D000107:Acetylation; D015704:CD4 Antigens / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D057809:HEK293 Cells; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
D015704:CD4 Antigens; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D054322:tat Gene Products, Human Immunodeficiency Virus; C447939:SIRT1 protein, human; D056564:Sirtuin 1