Ferri K F, Jacotot E, Blanco J, Esté J A, Kroemer G
Centre National de la Recherche Scientifique, UMR1599, Institut Gustave Roussy, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.
Ann N Y Acad Sci. 2000;926:149-64. doi: 10.1111/j.1749-6632.2000.tb05609.x.
In most examples of physiological or pathological cell death, mitochondrial membrane permeabilization (MMP) constitutes an early critical event of the lethal process. Signs of MMP that precede nuclear apoptosis include the translocation of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria to an extra-mitochondrial localization, as well as the dissipation of the mitochondrial transmembrane potential. MMP also occurs in HIV-1-induced apoptosis. Different HIV-1 encoded proteins (Env, Vpr, Tat, PR) can directly or indirectly trigger MMP, thereby causing cell death. The gp120/gp41 Env complex constitutes an example for an indirect MMP inducer. Env expressed on the plasma membrane of HIV-1 infected (or Env-transfected) cells mediates cell fusion with CD4/CXCR4-expressing uninfected cells. After a cell type-dependent latency period, syncytia then undergo MMP and apoptosis. Vpr exemplifies a direct MMP inducer. Vpr binds to the adenine nucleotide translocator (ANT), a mitochondrial inner membrane protein which also interacts with apoptosis-regulatory proteins from the Bcl-2/Bax family. Binding of Vpr to ANT favors formation of a non-specific pore leading to MMP. The structural motifs of the Vpr protein involved in MMP are conserved among most pathogenic HIV-1 isolates and determine the cytotoxic effect of Vpr. These data suggest the possibility that viruses employ multiple strategies to regulate host cell apoptosis by targeting mitochondria.
在大多数生理性或病理性细胞死亡的例子中,线粒体膜通透性改变(MMP)是致死过程早期的关键事件。在细胞核凋亡之前出现的MMP迹象包括细胞色素c和凋亡诱导因子(AIF)从线粒体转位至线粒体外区域,以及线粒体跨膜电位的消散。MMP也发生在HIV-1诱导的凋亡过程中。不同的HIV-1编码蛋白(Env、Vpr、Tat、PR)可直接或间接触发MMP,从而导致细胞死亡。gp120/gp41 Env复合物是间接MMP诱导剂的一个例子。在HIV-1感染(或Env转染)细胞的质膜上表达的Env介导与表达CD4/CXCR4的未感染细胞的细胞融合。经过细胞类型依赖的潜伏期后,多核巨细胞随后发生MMP和凋亡。Vpr是直接MMP诱导剂的一个例子。Vpr与腺嘌呤核苷酸转位酶(ANT)结合,ANT是一种线粒体内膜蛋白,它也与Bcl-2/Bax家族的凋亡调节蛋白相互作用。Vpr与ANT的结合有利于形成导致MMP的非特异性孔道。参与MMP的Vpr蛋白的结构基序在大多数致病性HIV-1分离株中是保守的,并决定了Vpr的细胞毒性作用。这些数据表明病毒可能通过靶向线粒体采用多种策略来调节宿主细胞凋亡。