Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type 1 envelope glycoprotein (gp120)
Caspase-dependent apoptosis of cells expressing the chemokine receptor CXCR4 is induced by cell membrane-associated human immunodeficiency virus type 1 envelope glycoprotein (gp120)
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DOI：
10.1006/viro.1999.0151
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发表时间：
2000-03-15
期刊：
影响因子：
3.7
通讯作者：
Devaux, C
中科院分区：
文献类型：
--
作者：
Biard-Piechaczyk, M;Robert-Hebmann, V;Devaux, C
人类免疫缺陷病毒 1 型 (HIV-1) 包膜糖蛋白与 T 细胞上的 CD4 和趋化因子受体相互作用，传递触发激活、无反应或凋亡的信号。然而，驱动这些反应的分子机制仍然知之甚少。在这项研究中，我们证明细胞凋亡是在HIV-1包膜与趋化因子受体CXCR4结合后诱导的。表达 C 末端缺失的 CXCR4 突变体的细胞也对 HIV-1 包膜介导的细胞凋亡敏感，表明 CXCR4 的细胞质尾部不需要诱导细胞凋亡途径。使用 gp120-CD4-CXCR4 相互作用的几种抑制剂分析了该过程的特异性。针对 CD4 (ST4) 上的 gp120 结合位点和 CXCR4 (MAB173) 的单克隆抗体以剂量依赖性方式阻止细胞凋亡信号。细胞死亡程序也受到 SDF-1 α（CXCR4 的天然配体）和苏拉明（一种 G 蛋白抑制剂，与 HIV-1 gp120 包膜蛋白的 V3 环具有高亲和力结合）的抑制。这些结果强调了 CXCR4 上的 gp120 结合在触发程序性细胞死亡中所发挥的作用。接下来，我们研究了 gp120 诱导的细胞凋亡中涉及的细胞内信号。该细胞死亡程序对百日咳毒素不敏感，不涉及应激和凋亡相关 MAP 激酶 p38(MAPK) 和 SAPK/JNK 的激活，但被广谱 caspase 抑制剂 (z-VAD.fmk) 和相对选择性的 caspase 3 抑制剂 (z-DEVD.fmk) 抑制。总而言之，我们的结果表明 HIV 通过 CXCR4 诱导 caspase 依赖性细胞凋亡信号通路。 (C) 2000 年学术出版社。
Human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins interact with CD4 and chemokine receptors on T cells to deliver signals that trigger either activation, anergy, or apoptosis. However, the molecular mechanisms driving these responses remain poorly understood. In this study we demonstrate that apoptosis is induced upon HIV-I envelope binding to the chemokine receptor CXCR4. Cells expressing a mutant form of CXCR4 with a C-terminal deletion were also sensitive to HIV-1 envelope-mediated apoptosis, indicating that the cytoplasmic tail of CXCR4 is not required to induce the apoptotic pathway. The specificity of this process was analyzed using several inhibitors of gp120-CD4-CXCR4 interaction. Monoclonal antibodies directed against the gp120-binding site on CD4 (ST4) and against CXCR4 (MAB173) prevented the apoptotic signal in a dose-dependent manner. The cell death program was also inhibited by SDF-1 alpha, the natural ligand of CXCR4, and by suramin, a G protein inhibitor that binds with a high affinity to the V3 loop of HIV-1 gp120 envelope protein. These results highlight the role played by gp120-binding on CXCR4 to trigger programmed cell death. Next, we investigated the intracellular signal involved in gp120-induced apoptosis. This cell death program was insensitive to pertussis toxin and did not involve activation of the stress- and apoptosis-related MAP kinases p38(MAPK) and SAPK/JNK but was inhibited by a broad spectrum caspase inhibitor (z-VAD.fmk) and a relatively selective inhibitor of caspase 3 (z-DEVD.fmk). Altogether, our results demonstrate that HIV induces a caspase-dependent apoptotic signaling pathway through CXCR4. (C) 2000 Academic Press.