Antagonism of tetherin restriction of HIV-1 release by Vpu involves binding and sequestration of the restriction factor in a perinuclear compartment
dc.contributor.author | Dubé, Mathieu | |
dc.contributor.author | Roy, Bibhuti Bhusan | |
dc.contributor.author | Guiot-Guillain, Pierre | |
dc.contributor.author | Binette, Julie | |
dc.contributor.author | Mercier, Johanne | |
dc.contributor.author | Chiasson, Antoine | |
dc.contributor.author | Cohen, Éric A. | |
dc.date.accessioned | 2010-12-19T22:04:29Z | |
dc.date.available | NO_RESTRICTION | en |
dc.date.available | 2010-12-19T22:04:29Z | |
dc.date.issued | 2010 | |
dc.identifier.uri | http://hdl.handle.net/1866/4486 | |
dc.title | Antagonism of tetherin restriction of HIV-1 release by Vpu involves binding and sequestration of the restriction factor in a perinuclear compartment | en |
dc.type | Article | en |
dc.contributor.affiliation | Université de Montréal. Faculté de médecine. Département de microbiologie, infectiologie et immunologie | fr |
dc.contributor.affiliation | Université de Montréal. Faculté de médecine. Institut de recherches cliniques de Montréal | fr |
dc.identifier.doi | 10.1371/journal.ppat.1000856 | |
dcterms.abstract | 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. | en |
dcterms.language | eng | en |
UdeM.VersionRioxx | Version acceptée / Accepted Manuscript | |
oaire.citationTitle | PLoS pathogens | |
oaire.citationVolume | 6 | |
oaire.citationIssue | 4 |
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