HIV-1 Vpr-induced apoptosis is cell cycle dependent and requires Bax but not ANT.
HIV-1 Vpr-induced apoptosis is cell cycle dependent and requires Bax but not ANT.
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DOI：
10.1371/journal.ppat.0020127
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发表时间：
2006-12
期刊：
影响因子：
6.7
通讯作者：
Planelles V
中科院分区：
文献类型：
--
作者：
Andersen JL;DeHart JL;Zimmerman ES;Ardon O;Kim B;Jacquot G;Benichou S;Planelles V
HIV-1 辅助蛋白病毒蛋白 R (Vpr) 会导致受感染细胞的 G2 期停滞和细胞凋亡。我们之前发现 DNA 损伤信号蛋白 ATR 是介导 Vpr 诱导的 G2 停滞和细胞凋亡的细胞因子。在这里，我们研究了 Vpr 诱导细胞凋亡的机制及其与诱导 G2 停滞的关系。我们发现进入 G2 是 Vpr 诱导细胞凋亡的必要条件。我们通过敲低线粒体通透性转换孔的基本成分腺嘌呤核苷酸易位子来研究线粒体通透性转换孔的作用。我们发现Vpr诱导的细胞凋亡不受ANT敲除的影响。相反，细胞凋亡是通过不同的线粒体孔蛋白 Bax 触发的。为了支持检查点激活和细胞凋亡诱导在功能上相关的观点，我们发现当 ATR 或 GADD45α 被敲低时，Vpr 激活的 Bax 被消除。在长期非进展者中发现的 Vpr 的某些突变体，如 R77Q 和 I74A，已被认为在以正常方式激活 G2 检查点的同时，不能有效地诱导细胞凋亡。我们测试了这些突变体的体外表型，发现它们诱导细胞凋亡和 G2 期停滞的能力与 HIV-1NL4-3 vpr 没有区别，这为 G2 期停滞和细胞凋亡诱导在机制上相关的观点提供了额外的支持。 HIV-1 编码一个称为 vpr（病毒蛋白调节）的小基因，其产物是 96 个氨基酸的蛋白质。 HIV-1 感染免疫系统细胞，例如 CD4 阳性淋巴细胞。当细胞感染 HIV-1 时，vpr 基因的表达会产生两种有害影响。 vpr 的作用之一是通过阻断 G2（有丝分裂之前的细胞周期阶段）细胞来操纵细胞周期。因此，由于 vpr 的作用，感染 HIV-1 的细胞停止增殖。 vpr 的第二个作用是通过称为细胞凋亡或程序性细胞死亡的过程诱导细胞死亡。当细胞因凋亡而死亡时，它们会在一组细胞基因和蛋白质激活后死亡，这些基因和蛋白质的主要功能是使维持细胞活力所需的各种细胞功能失活。在这项研究中，安德森等人。证明 vpr 的上述两种效应是相互关联的。特别是，作者表明，G2 期细胞增殖的阻断是程序性细胞死亡开始的必要条件。程序性细胞死亡可以通过许多被称为“刽子手”的细胞蛋白质来完成。各种刽子手蛋白驻留在线粒体膜上，可能会触发线粒体释放因子，进而促进细胞凋亡的发生。在这项工作中，安德森等人。确定线粒体蛋白 Bax 是 HIV-1 vpr 中细胞凋亡的关键执行者。作者的发现为 vpr 基因如何促进 HIV-1 诱导的细胞死亡提供了重要的机制理解。
The HIV-1 accessory protein viral protein R (Vpr) causes G2 arrest and apoptosis in infected cells. We previously identified the DNA damage–signaling protein ATR as the cellular factor that mediates Vpr-induced G2 arrest and apoptosis. Here, we examine the mechanism of induction of apoptosis by Vpr and how it relates to induction of G2 arrest. We find that entry into G2 is a requirement for Vpr to induce apoptosis. We investigated the role of the mitochondrial permeability transition pore by knockdown of its essential component, the adenine nucleotide translocator. We found that Vpr-induced apoptosis was unaffected by knockdown of ANT. Instead, apoptosis is triggered through a different mitochondrial pore protein, Bax. In support of the idea that checkpoint activation and apoptosis induction are functionally linked, we show that Bax activation by Vpr was ablated when ATR or GADD45α was knocked down. Certain mutants of Vpr, such as R77Q and I74A, identified in long-term nonprogressors, have been proposed to inefficiently induce apoptosis while activating the G2 checkpoint in a normal manner. We tested the in vitro phenotypes of these mutants and found that their abilities to induce apoptosis and G2 arrest are indistinguishable from those of HIV-1NL4–3 vpr, providing additional support to the idea that G2 arrest and apoptosis induction are mechanistically linked. HIV-1 encodes a small gene known as vpr (viral protein regulatory) whose product is a 96–amino acid protein. HIV-1 infects cells of the immune system, such as CD4-positive lymphocytes. When cells become infected with HIV-1, two deleterious effects result from expression of the vpr gene. One effect of vpr is to manipulate the cell cycle by blocking the cells in G2 (the phase of the cell cycle immediately preceding mitosis). Thus, cells infected with HIV-1 cease to proliferate, due to the action of vpr. A second effect of vpr is the induction of cell death by a process known as apoptosis or programmed cell death. When cells die by apoptosis, they do so following activation of a cellular set of genes and proteins whose primary function is to inactivate various cellular functions that are needed in order to maintain cellular viability. In this study, Andersen et al. demonstrate that the above two effects of vpr are linked. In particular, the authors show that the blockade in cell proliferation in G2 is a requirement toward the onset of programmed cell death. Programmed cell death can be accomplished by a number of cellular proteins known as “executioners.” Various executioner proteins reside on the mitochondrial membranes and may trigger release of factors from the mitochondria, which in turn will precipitate the onset of apoptosis. In this work Anderson et al. identify the mitochondrial protein, Bax, as the key executioner of apoptosis in the context of HIV-1 vpr. The authors' findings provide important mechanistic understanding of how the vpr gene contributes to HIV-1–induced cell death.
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影响因子：
5.4
作者：
An, DS;Morizono, K;Chen, ISY
通讯作者：
Chen, ISY
影响因子：
5.4
作者：
Ardon, O;Zimmerman, ES;Planelles, V
通讯作者：
Planelles, V
DOI：
10.1073/pnas.0504222102
发表时间：
2005-07-05
影响因子：
11.1
作者：
Ishii, H;Inageta, T;Furukawa, Y
通讯作者：
Furukawa, Y
影响因子：
5.4
作者：
DIMARZIO, P;CHOE, S;LANDAU, NR
通讯作者：
LANDAU, NR
影响因子：
11.2
作者：
Hammond, EM;Dorie, MJ;Giaccia, AJ
通讯作者：
Giaccia, AJ