Human immunodeficiency virus 1 envelope glycoprotein complex-induced apoptosis involves mammalian target of rapamycin/FKBP12-rapamycin-associated protein-mediated p53 phosphorylation.
Human immunodeficiency virus 1 envelope glycoprotein complex-induced apoptosis involves mammalian target of rapamycin/FKBP12-rapamycin-associated protein-mediated p53 phosphorylation.
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DOI：
10.1084/jem.194.8.1097
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发表时间：
2001-10-15
期刊：
影响因子：
--
通讯作者：
Kroemer G
中科院分区：
文献类型：
--
作者：
Castedo M;Ferri KF;Blanco J;Roumier T;Larochette N;Barretina J;Amendola A;Nardacci R;Métivier D;Este JA;Piacentini M;Kroemer G
表达嗜淋巴细胞性人类免疫缺陷病毒（HIV）-1编码的包膜糖蛋白复合物（Env）基因的细胞与表达CD 4/CXCR 4复合物的细胞融合产生的合胞体通过Bax上调启动的线粒体控制途径进行细胞凋亡。在合胞体细胞凋亡中，p53丝氨酸15（p53 S15）磷酸化先于Bax上调，Bax的凋亡相关构象变化，Bax在线粒体膜中的插入，随后释放细胞色素c，caspase激活和细胞凋亡。p53 S15磷酸化也发生在体内，在HIV-1+供体中，可以在淋巴结中的凋亡前和凋亡合胞体中以及外周血单核细胞中检测到，与病毒载量相关。合胞体诱导的p53 S15磷酸化是通过上调/激活哺乳动物雷帕霉素靶蛋白（mTOR）介导的，mTOR也称为FKBP 12-雷帕霉素相关蛋白（FRAP），其与p53共免疫沉淀。雷帕霉素对mTOR/FRAP的抑制减少了合胞体依赖性死亡的几种范例中的细胞凋亡，包括HIV-1感染的原代CD 4+淋巴母细胞。同时，雷帕霉素抑制p53 S15磷酸化、Bax的线粒体易位、线粒体跨膜电位的丧失、细胞色素c的线粒体释放和核染色质凝聚。显性负性p53转染具有与雷帕霉素类似的抗凋亡作用，在Bax上调/易位的上游。总之，我们证明了mTOR/FRAP对p53 S15的磷酸化在HIV-1 Env驱动的合胞体凋亡中起着关键作用。
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.
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影响因子：
3.7
作者：
Ferri, KF;Jacotot, E;Kroemer, G
通讯作者：
Kroemer, G
影响因子：
7.5
作者：
Dargent, JL;Lespagnard, L;Verhest, A
通讯作者：
Verhest, A
DOI：
10.1073/pnas.94.9.4653
发表时间：
1997-04-29
影响因子：
11.1
作者：
Gervaix, A;West, D;Corbeil, J
通讯作者：
Corbeil, J
影响因子：
4.8
作者：
Chan, DW;Son, SC;Lees-Miller, SP
通讯作者：
Lees-Miller, SP
DOI：
10.1073/pnas.97.15.8501
发表时间：
2000-07-18
影响因子：
11.1
作者：
Hietanen, S;Lain, S;Lane, DP
通讯作者：
Lane, DP