HIV-1 Nef and Vpu Are Functionally Redundant Broad-Spectrum Modulators of Cell Surface Receptors, Including Tetraspanins
HIV-1 Nef and Vpu Are Functionally Redundant Broad-Spectrum Modulators of Cell Surface Receptors, Including Tetraspanins
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DOI：
10.1128/jvi.02333-14
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发表时间：
2014-12-01
影响因子：
5.4
通讯作者：
Fackler, Oliver T.
中科院分区：
文献类型：
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作者：
Haller, Claudia;Mueller, Birthe;Fackler, Oliver T.
HIV-1 Nef和Vpu被认为至少部分通过其干扰囊泡宿主细胞运输的能力来优化感染宿主中的病毒复制。尽管使用不同的分子机制，Nef和Vpu共享的一些分子，如CD 4和主要组织相容性复合物I类（MHC-I）的特异性，而宿主细胞限制因子CD 317/tetherin的细胞内转运的破坏代表了一个专门的活动Vpu不发挥HIV-1 Nef。为了建立其细胞内转运受Nef、Vpu或两者影响的宿主细胞受体的概况，我们全面分析了这些辅助病毒蛋白对A3.01 T淋巴细胞上的细胞表面受体水平的影响。在105个可检测的受体中，有36个被HIV-1 Nef显著下调，揭示了HIV-1 Nef重塑感染细胞表面的一个以前未被认识到的范围。值得注意的是，HIV-1 Vpu对宿主细胞受体暴露的影响在广度和特异性上与HIV-1 Nef的影响基本匹配（105个中的32个，也都是Nef的靶向），尽管幅度通常不那么明显。特别值得注意的是，Nef和Vpu均降低了所分析的四跨膜蛋白（TSPAN）蛋白家族所有成员的细胞表面暴露，并且病毒蛋白引发了TSPAN在细胞核周区域的富集。虽然Vpu与TSPAN显示出显著的共定位和物理关联，但Nef与TSPAN的相互作用不太稳健。因此，TSPAN成为HIV-1 Nef和Vpu解除宿主细胞囊泡转运调节的主要靶点。这种活动在两个独立的辅助蛋白的保护表明其重要性的传播HIV-1在受感染的host.IMPORTANCEIn本文中，我们定义的HIV-1 Nef和Vpu显示一个令人惊讶的功能重叠和影响细胞表面暴露的一个以前意想不到的广度的细胞受体。我们的分析进一步确定四跨膜蛋白家族作为Nef和Vpu活性的先前未识别的靶标。这些研究结果的解释，这些辅助基因产物对个体宿主细胞受体的影响，并说明Nef和Vpu功能的共同进化。
HIV-1 Nef and Vpu are thought to optimize virus replication in the infected host, at least in part via their ability to interfere with vesicular host cell trafficking. Despite the use of distinct molecular mechanisms, Nef and Vpu share specificity for some molecules such as CD4 and major histocompatibility complex class I (MHC-I), while disruption of intracellular transport of the host cell restriction factor CD317/tetherin represents a specialized activity of Vpu not exerted by HIV-1 Nef. To establish a profile of host cell receptors whose intracellular transport is affected by Nef, Vpu, or both, we comprehensively analyzed the effect of these accessory viral proteins on cell surface receptor levels on A3.01 T lymphocytes. Thirty-six out of 105 detectable receptors were significantly downregulated by HIV-1 Nef, revealing a previously unappreciated scope with which HIV-1 Nef remodels the cell surface of infected cells. Remarkably, the effects of HIV-1 Vpu on host cell receptor exposure largely matched those of HIV-1 Nef in breadth and specificity (32 of 105, all also targeted by Nef), even though the magnitude was generally less pronounced. Of particular note, cell surface exposure of all members of the tetraspanin (TSPAN) protein family analyzed was reduced by both Nef and Vpu, and the viral proteins triggered the enrichment of TSPANs in a perinuclear area of the cell. While Vpu displayed significant colocalization and physical association with TSPANs, interactions of Nef with TSPANs were less robust. TSPANs thus emerge as a major target of deregulation in host cell vesicular transport by HIV-1 Nef and Vpu. The conservation of this activity in two independent accessory proteins suggests its importance for the spread of HIV-1 in the infected host.IMPORTANCEIn this paper, we define that HIV-1 Nef and Vpu display a surprising functional overlap and affect the cell surface exposure of a previously unexpected breadth of cellular receptors. Our analyses furthermore identify the tetraspanin protein family as a previously unrecognized target of Nef and Vpu activity. These findings have implications for the interpretation of effects detected for these accessory gene products on individual host cell receptors and illustrate the coevolution of Nef and Vpu function.