Human immunodeficiency virus 1 envelope glycoprotein complex-induced apoptosis involves mammalian target of rapamycin/FKBP12-rapamycin-associated protein-mediated p53 phosphorylation.
Syncytia arising from the fusion of cells expressing a lymphotropic human immunodeficiency virus (HIV)-1-encoded envelope glycoprotein complex (Env) gene with cells expressing the CD4/CXCR4 complex undergo apoptosis through a mitochondrion-controlled pathway initiated by the upregulation of Bax. In syncytial apoptosis, phosphorylation of p53 on serine 15 (p53S15) precedes Bax upregulation, the apoptosis-linked conformational change of Bax, the insertion of Bax in mitochondrial membranes, subsequent release of cytochrome c, caspase activation, and apoptosis. p53S15 phosphorylation also occurs in vivo, in HIV-1(+) donors, where it can be detected in preapoptotic and apoptotic syncytia in lymph nodes, as well as in peripheral blood mononuclear cells, correlating with viral load. Syncytium-induced p53S15 phosphorylation is mediated by the upregulation/activation of mammalian target of rapamycin (mTOR), also called FKBP12-rapamycin-associated protein (FRAP), which coimmunoprecipitates with p53. Inhibition of mTOR/FRAP by rapamycin reduces apoptosis in several paradigms of syncytium-dependent death, including in primary CD4(+) lymphoblasts infected by HIV-1. Concomitantly, rapamycin inhibits p53S15 phosphorylation, mitochondrial translocation of Bax, loss of the mitochondrial transmembrane potential, mitochondrial release of cytochrome c, and nuclear chromatin condensation. Transfection with dominant negative p53 has a similar antiapoptotic action as rapamycin, upstream of the Bax upregulation/translocation. In summary, we demonstrate that phosphorylation of p53S15 by mTOR/FRAP plays a critical role in syncytial apoptosis driven by HIV-1 Env.
Castedo
M
M
Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, F-94805 Villejuif, France.
Ferri
K F
KF
Blanco
J
J
Roumier
T
T
Larochette
N
N
Barretina
J
J
Amendola
A
A
Nardacci
R
R
Métivier
D
D
Este
J A
JA
Piacentini
M
M
Kroemer
G
G
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002352:Carrier Proteins; D015726:Giant Cells; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D020104:Immunophilins / Q000276:immunology*; D008322:Mammals; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor); D012694:Serine / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D002352:Carrier Proteins; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D016159:Tumor Suppressor Protein p53; D012694:Serine; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020104:Immunophilins