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dc.contributor.authorDubé, Mathieu
dc.contributor.authorRoy, Bibhuti Bhusan
dc.contributor.authorGuiot-Guillain, Pierre
dc.contributor.authorBinette, Julie
dc.contributor.authorMercier, Johanne
dc.contributor.authorChiasson, Antoine
dc.contributor.authorCohen, Éric A.
dc.date.accessioned2010-12-19T22:04:29Z
dc.date.availableNO_RESTRICTIONen
dc.date.available2010-12-19T22:04:29Z
dc.date.issued2010
dc.identifier.urihttp://hdl.handle.net/1866/4486
dc.titleAntagonism of tetherin restriction of HIV-1 release by Vpu involves binding and sequestration of the restriction factor in a perinuclear compartmenten
dc.typeArticleen
dc.contributor.affiliationUniversité de Montréal. Faculté de médecine. Département de microbiologie, infectiologie et immunologiefr
dc.contributor.affiliationUniversité de Montréal. Faculté de médecine. Institut de recherches cliniques de Montréalfr
dc.identifier.doi10.1371/journal.ppat.1000856
dcterms.abstractThe 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.languageengen
UdeM.VersionRioxxVersion acceptée / Accepted Manuscript
oaire.citationTitlePLoS pathogens
oaire.citationVolume6
oaire.citationIssue4


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