Vpu downmodulates two distinct targets, tetherin and gibbon ape leukemia virus envelope, through shared features in the Vpu cytoplasmic tail.
Vpu downmodulates two distinct targets, tetherin and gibbon ape leukemia virus envelope, through shared features in the Vpu cytoplasmic tail.
复制标题
DOI：
10.1371/journal.pone.0051741
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Johnson MC
中科院分区：
文献类型：
--
作者：
Lucas TM;Janaka SK;Stephens EB;Johnson MC
在人类免疫缺陷病毒-1（HIV-1）组装期间，宿主蛋白CD 4（HIV-1受体）和系链蛋白（一种干扰素刺激的抗病毒蛋白）都降低了病毒适应性。HIV-1辅助基因Vpu抵消了这两种蛋白质，但它被认为是通过两种不同的机制来实现的。CD 4的调节可能通过内质网的蛋白酶体降解而发生。栓系蛋白调节的确切机制尚不清楚，可能与降解和改变蛋白质转运到质膜有关。大多数Vpu功能的研究使用了不同的CD 4和tetherin测定法。此外，许多这些研究使用外源表达的Vpu，这可能导致可变的表达水平。因此，很少有研究在平行测定中研究这两种Vpu功能，使得直接比较困难。在这里，我们提出了一种快速检测的结果，用于同时调查Vpu靶向的系链蛋白和病毒糖蛋白，巨猿白血病病毒包膜（GaLV Env）。我们以前报道过，Vpu调节GaLV Env，并通过类似于CD 4中发现的识别基序阻止其掺入HIV-1颗粒。使用该测定，我们在其天然前病毒背景下对Vpu进行了全面的诱变扫描，以鉴定两种类型活性所需的特征。我们观察到相当大的重叠，在Vpu序列所需的调制tetherin和GaLV Env。我们发现Vpu的胞质尾区的特征，特别是胞质尾区铰链区内的特征，是调节系链蛋白和GaLV Env所必需的。有趣的是，这些相同的区域特征已被确定为对CD 4下调至关重要。我们还观察到的跨膜结构域的限制的拴，如前所述，但没有的GaLV Env的作用。我们建议，Vpu可能以类似的方式靶向这两种蛋白质，尽管在不同的细胞位置。
During human immunodeficiency virus-1 (HIV-1) assembly, the host proteins CD4 (the HIV-1 receptor) and tetherin (an interferon stimulated anti-viral protein) both reduce viral fitness. The HIV-1 accessory gene Vpu counteracts both of these proteins, but it is thought to do so through two distinct mechanisms. Modulation of CD4 likely occurs through proteasomal degradation from the endoplasmic reticulum. The exact mechanism of tetherin modulation is less clear, with possible roles for degradation and alteration of protein transport to the plasma membrane. Most investigations of Vpu function have used different assays for CD4 and tetherin. In addition, many of these investigations used exogenously expressed Vpu, which could result in variable expression levels. Thus, few studies have investigated these two Vpu functions in parallel assays, making direct comparisons difficult. Here, we present results from a rapid assay used to simultaneously investigate Vpu-targeting of both tetherin and a viral glycoprotein, gibbon ape leukemia virus envelope (GaLV Env). We previously reported that Vpu modulates GaLV Env and prevents its incorporation into HIV-1 particles through a recognition motif similar to that found in CD4. Using this assay, we performed a comprehensive mutagenic scan of Vpu in its native proviral context to identify features required for both types of activity. We observed considerable overlap in the Vpu sequences required to modulate tetherin and GaLV Env. We found that features in the cytoplasmic tail of Vpu, specifically within the cytoplasmic tail hinge region, were required for modulation of both tetherin and GaLV Env. Interestingly, these same regions features have been determined to be critical for CD4 downmodulation. We also observed a role for the transmembrane domain in the restriction of tetherin, as previously reported, but not of GaLV Env. We propose that Vpu may target both proteins in a mechanistically similar manner, albeit in different cellular locations.
登录
查看更多内容
影响因子：
5.4
作者：
Hussain, Amjad;Wesley, Clement;Jameel, Shahid
通讯作者：
Jameel, Shahid
影响因子：
5.4
作者：
CHEN, MY;MALDARELLI, F;STREBEL, K
通讯作者：
STREBEL, K
影响因子：
6.7
作者：
Dubé M;Roy BB;Guiot-Guillain P;Binette J;Mercier J;Chiasson A;Cohen EA
通讯作者：
Cohen EA
影响因子：
3.3
作者：
Hauser H;Lopez LA;Yang SJ;Oldenburg JE;Exline CM;Guatelli JC;Cannon PM
通讯作者：
Cannon PM
影响因子：
3.7
作者：
Hout, DR;Gomez, ML;Stephens, EB
通讯作者：
Stephens, EB