Antagonism of Tetherin Restriction of HIV-1 Release by Vpu Involves Binding and Sequestration of the Restriction Factor in a Perinuclear Compartment

被引:179
作者
Dube, Mathieu [1 ]
Roy, Bibhuti Bhusan [1 ]
Guiot-Guillain, Pierre [1 ]
Binette, Julie [1 ]
Mercier, Johanne [1 ]
Chiasson, Antoine [1 ]
Cohen, Eric A. [1 ,2 ]
机构
[1] Inst Rech Clin Montreal, Lab Human Retrovirol, Montreal, PQ H2W 1R7, Canada
[2] Univ Montreal, Dept Microbiol & Immunol, Montreal, PQ H3C 3J7, Canada
基金
加拿大健康研究院;
关键词
IMMUNODEFICIENCY-VIRUS TYPE-1; CELL-SURFACE; INHIBITS HIV-1; FUNCTIONAL-ANALYSIS; PARTICLE RELEASE; DOWN-MODULATION; BETA-TRCP; PROTEIN; DEGRADATION; CD4;
D O I
10.1371/journal.ppat.1000856
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The Vpu accessory protein promotes HIV-1 release by counteracting Tetherin/BST-2, an interferon-regulated restriction factor, which retains virions at the cell-surface. Recent reports proposed beta-TrCP-dependent proteasomal and/or endo-lysosomal degradation of Tetherin as potential mechanisms by which Vpu could down-regulate Tetherin cell-surface expression and antagonize this restriction. In all of these studies, Tetherin degradation did not, however, entirely account for Vpu anti-Tetherin activity. Here, we show that Vpu can promote HIV-1 release without detectably affecting Tetherin steady-state levels or turnover, suggesting that Tetherin degradation may not be necessary and/or sufficient for Vpu anti-Tetherin activity. Even though Vpu did not enhance Tetherin internalization from the plasma membrane (PM), it did significantly slow-down the overall transport of the protein towards the cell-surface. Accordingly, Vpu expression caused a specific removal of cell-surface Tetherin and a re-localization of the residual pool of Tetherin in a perinuclear compartment that co-stained with the TGN marker TGN46 and Vpu itself. This re-localization of Tetherin was also observed with a Vpu mutant unable to recruit beta-TrCP, suggesting that this activity is taking place independently from beta-TrCP-mediated trafficking and/or degradation processes. We also show that Vpu co-immunoprecipitates with Tetherin and that this interaction involves the transmembrane domains of the two proteins. Importantly, this association was found to be critical for reducing cell-surface Tetherin expression, re-localizing the restriction factor in the TGN and promoting HIV-1 release. Overall, our results suggest that association of Vpu to Tetherin affects the outward trafficking and/or recycling of the restriction factor from the TGN and as a result promotes its sequestration away from the PM where productive HIV-1 assembly takes place. This mechanism of antagonism that results in TGN trapping is likely to be augmented by beta-TrCP-dependent degradation, underlining the need for complementary and perhaps synergistic strategies to effectively counteract the powerful restrictive effects of human Tetherin.
引用
收藏
页码:1 / 19
页数:19
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