The ESCRT-0 component HRS is required for HIV-1 Vpu-mediated BST-2/tetherin down-regulation.
The ESCRT-0 component HRS is required for HIV-1 Vpu-mediated BST-2/tetherin down-regulation.
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DOI：
10.1371/journal.ppat.1001265
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发表时间：
2011-02-03
期刊：
影响因子：
6.7
通讯作者：
Berlioz-Torrent C
中科院分区：
文献类型：
--
作者：
Janvier K;Pelchen-Matthews A;Renaud JB;Caillet M;Marsh M;Berlioz-Torrent C
转运所需的内体分选复合物（ESCRT）机制是一组高度保守的四种异源寡聚蛋白复合物，其是多泡体形成、分选用于溶酶体降解的泛素化膜蛋白、胞质分裂和许多包膜病毒（包括人类免疫缺陷病毒）组装的最后阶段所需的。在这里，我们展示了ESCRT机制在HIV-1释放中的额外作用。BST-2/tetherin是一种限制因子，通过将成熟病毒颗粒束缚在质膜上来阻止HIV释放。我们发现，HRS，ESCRT-0复合物的关键组成部分，促进HIV-1的有效释放，siRNA介导的HRS消耗诱导BST-2/tetherin表型。这种活性与HIV-1 Vpu蛋白下调BST-2/tetherin的能力有关。我们发现BST-2/tetherin经历了组成型ESCRT依赖性的溶酶体降解分选，并且这种降解通过Vpu表达增强。我们证明了Vpu介导的BST-2/tetherin下调和降解需要HRS（ESCRT-0）功能，HRS的敲低增加了BST-2/tetherin的细胞水平并限制了病毒释放。此外，HRS与Vpu和BST-2共沉淀。我们的研究结果进一步深入了解了Vpu抵消BST-2/tetherin并促进HIV-1传播的机制，并强调了ESCRT机制在病毒释放中的额外作用。HIV-1颗粒的释放需要病毒编码的蛋白质与关键细胞组分之间的一系列相互作用，包括细胞膜运输装置的元件，如运输所需的内体分选复合物（ESCRT）机制。这种机制由四种多蛋白复合物（ESCRT-0，-I，-II和-III）组成，它们参与了溶酶体降解泛素化膜蛋白的分选。Gag是HIV的主要结构蛋白，募集ESCRT-I和III复合物来介导出芽病毒体的断裂。在ESCRT介导的病毒颗粒的断裂之后，HIV-1辅助蛋白Vpu通过抵消细胞限制因子BST-2/系链蛋白（tetherin）促进成熟病毒体的释放，所述细胞限制因子BST-2/系链蛋白将病毒颗粒物理地束缚到感染细胞的质膜。在这里，我们表明，HRS，ESCRT-0复合物的一个组成部分，需要Vpu有效地调节BST-2的表达和促进HIV-1的释放，突出了ESCRT机制在病毒生产中的额外作用。
The Endosomal Sorting Complexes Required for Transport (ESCRT) machinery, a highly conserved set of four hetero-oligomeric protein complexes, is required for multivesicular body formation, sorting ubiquitinylated membrane proteins for lysosomal degradation, cytokinesis and the final stages of assembly of a number of enveloped viruses, including the human immunodeficiency viruses. Here, we show an additional role for the ESCRT machinery in HIV-1 release. BST-2/tetherin is a restriction factor that impedes HIV release by tethering mature virus particles to the plasma membrane. We found that HRS, a key component of the ESCRT-0 complex, promotes efficient release of HIV-1 and that siRNA-mediated HRS depletion induces a BST-2/tetherin phenotype. This activity is related to the ability of the HIV-1 Vpu protein to down-regulate BST-2/tetherin. We found that BST-2/tetherin undergoes constitutive ESCRT-dependent sorting for lysosomal degradation and that this degradation is enhanced by Vpu expression. We demonstrate that Vpu-mediated BST-2/tetherin down-modulation and degradation require HRS (ESCRT-0) function and that knock down of HRS increases cellular levels of BST-2/tetherin and restricts virus release. Furthermore, HRS co-precipitates with Vpu and BST-2. Our results provide further insight into the mechanism by which Vpu counteracts BST-2/tetherin and promotes HIV-1 dissemination, and they highlight an additional role for the ESCRT machinery in virus release. The release of HIV-1 particles requires a series of interactions between proteins encoded by the virus and key cellular components, including elements of the cellular membrane trafficking apparatus such as the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery. This machinery is composed of four multiprotein complexes (ESCRT-0, -I, -II and –III) that are involved in the sorting of ubiquitinylated membrane proteins for lysosomal degradation. Gag, the major structural protein of HIV, recruits the ESCRT-I and III complexes to mediate the scission of budding virions. Following ESCRT-mediated scission of viral particles, the HIV-1 accessory protein Vpu promotes the release of the mature virions by counteracting a cellular restriction factor BST-2/tetherin that physically tethers viral particles to the plasma membrane of infected cells. Here we show that HRS, a component of the ESCRT-0 complex, is required for Vpu to efficiently modulate the expression of BST-2 and promote HIV-1 release, highlighting an additional role of the ESCRT machinery in virus production.
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DOI：
10.1083/jcb.200609050
发表时间：
2007-04-23
期刊：
The Journal of cell biology
影响因子：
--
作者：
Deneka M;Pelchen-Matthews A;Byland R;Ruiz-Mateos E;Marsh M
通讯作者：
Marsh M
影响因子：
6.7
作者：
Estrabaud, Emilie;Le Rouzic, Erwann;Margottin-Goguet, Florence
通讯作者：
Margottin-Goguet, Florence
影响因子：
30.3
作者：
Goffinet, Christine;Allespach, Ina;Keppler, Oliver T.
通讯作者：
Keppler, Oliver T.
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