HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell
HIV-1 Nef inhibits ASK1-dependent death signalling providing a potential mechanism for protecting the infected host cell
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DOI：
10.1038/35071111
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发表时间：
2001-04-12
期刊：
影响因子：
64.8
通讯作者：
Greene, WC
中科院分区：
文献类型：
--
作者：
Geleziunas, R;Xu, WD;Greene, WC
人体免疫缺陷病毒1型（HIV-1）在体内感染淋巴组织导致细胞凋亡增强，其中主要涉及未感染的旁观者细胞（1-3）。这种旁观者细胞的杀伤增加部分是通过Nef诱导病毒感染的T细胞表面Fas配体（FasL）表达（4-6）介导的。FasL随后与邻近细胞（包括hiv -1特异性细胞毒性T淋巴细胞）上显示的Fas （CD95）相互作用，可能导致旁观者细胞死亡，从而形成免疫逃避的重要机制。由于HIV-1也增强Fas在病毒感染细胞上的表达（7-9），这些宿主如何避免FasL顺式连接Fas介导的快速细胞自主凋亡尚不清楚。在这里，我们发现HIV-1 Nef与凋亡信号调节激酶1 （ASK1）相关并抑制凋亡信号调节激酶1 (ASK1)， ASK1是一种丝氨酸/苏氨酸激酶，在Fas和肿瘤坏死因子- α (TNF α)死亡信号通路中形成一种常见和关键的信号传导介质（10-12）。Nef与ASK1的相互作用抑制Fas-和TNF -介导的细胞凋亡，以及下游c-Jun氨基末端激酶的激活。我们的研究结果揭示了一种策略，即HIV-1 Nef通过诱导FasL促进旁观者细胞的杀伤，同时通过干扰ASK1功能保护HIV-1感染的宿主细胞免受这些促凋亡信号的影响。
In vivo infection of lymphatic tissues by the human immunodeficiency virus type 1 (HIV-1) leads to enhanced apoptosis, which prominently involves uninfected bystander cells(1-3). Increased killing of such bystander cells is mediated in part through Nef induction of Fas ligand (FasL) expression(4-6) on the surface of the virally infected T cells. The subsequent interaction of FasL with Fas (CD95) displayed on neighbouring cells, including HIV-1-specific cytotoxic T lymphocytes, may lead to bystander cell killing and thus forms an important mechanism of immune evasion. As HIV-1 also enhances Fas expression on virally infected cells(7-9), it is unclear how these hosts avoid rapid cell-autonomous apoptosis mediated through cis ligation of Fas by FasL. Here we show that HIV-1 Nef associates with and inhibits apoptosis signal-regulating kinase 1 (ASK1), a serine/threonine kinase that forms a common and key signalling intermediate in the Fas and tumour-necrosis factor-alpha (TNF alpha) death-signalling pathways(10-12). The interaction of Nef with ASK1 inhibits both Fas- and TNF alpha -mediated apoptosis, as well as the activation of the downstream c-Jun amino-terminal kinase. Our findings reveal a strategy by which HIV-1 Nef promotes the killing of bystander cells through the induction of FasL, while simultaneously protecting the HIV-1-infected host cell from these same pro-apoptotic signals through its interference with ASK1 function.