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- W2000586324 abstract "The primary roles attributed to the HIV-1 Vpu protein are the targeted downregulation of the viral receptor CD4 and the enhancement of virion release. With regards to CD4 degradation, Vpu has been shown to act as an adaptor linking CD4 with the ubiquitin/proteasome machinery via interaction with the F-box protein βTrCP. This interaction was previously thought to be dispensable for Vpu's virion release function. In an attempt to identify other cellular βTrCP-dependent Vpu targets, we performed quantitative proteomics on the plasma membrane fraction of Hela cells expressing either a wildtype Vpu, or a Vpu double point mutant (S52N/S56N) that no longer binds to βTrCP. We identified one cellular protein, BST-2 (CD317), that was significantly downregulated by wildtype Vpu, but not the mutant. Recently, BST-2 has been identified as the IFN-inducible cellular factor Tetherin, which limits HIV virion release in the absence of Vpu. We address here the mechanism of Vpu-mediated BST-2 downregulation. To verify the biological relevance of this phenotype, we show that in T-cells infected with HIV-1, BST-2 downregulation does indeed occur and is Vpu dependent. Interestingly, HIV-2, which does not encode Vpu, did not downregulate BST-2. Because our screen was designed to identify those proteins downregulated by Vpu in a βTrCP-dependent manner, we next sought to determine if Vpu targets BST-2 for degradation. We show via immunofluorescence and co-immunoprecipitations that both wildtype and mutant Vpu are able to interact with BST-2, but only wildtype Vpu results in BST-2 degradation. Further support for βTrCP's role was provided by showing that the dominant negative mutant ΔF-βTrCP, which can no longer interact with the SCF ubiquitin ligase complex, blocks Vpu's ability to downregulate BST-2. In addition, treatment of cells with either the proteasome inhibitor MG132 or the lysosome acidification inhibitor concanamycin A reduces BST-2 downregulation by wildtype Vpu. Taken together, these data support the hypothesis that, similar to its role in CD4 degradation, Vpu acts as an adaptor molecule linking BST-2 to the cellular ubiquitination machinery via βTrCP. This interaction then leads to the degradation of BST-2, which prevents viral tethering and therefore results in enhanced virion release." @default.
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- W2000586324 date "2009-06-01" @default.
- W2000586324 modified "2023-09-25" @default.
- W2000586324 title "115 HIV Vpu complexes with βTrCP to direct the degradation of the virus release inhibitor BST-2 (Tetherin)" @default.
- W2000586324 doi "https://doi.org/10.1097/01.qai.0000351072.82085.3f" @default.
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