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Human Immunodeficiency Virus Type 1 Vpr Mediates Degradation of APC1, a Scaffolding Component of the Anaphase-Promoting Complex/Cyclosome.
Barbosa, Jérémy A Ferreira; Sparapani, Samantha; Boulais, Jonathan; Lodge, Robert; Cohen, Éric A.
Afiliação
  • Barbosa JAF; Montreal Clinical Research Institute, Montréal, Québec, Canada.
  • Sparapani S; Montreal Clinical Research Institute, Montréal, Québec, Canada.
  • Boulais J; Montreal Clinical Research Institute, Montréal, Québec, Canada.
  • Lodge R; Montreal Clinical Research Institute, Montréal, Québec, Canada.
  • Cohen ÉA; Montreal Clinical Research Institute, Montréal, Québec, Canada.
J Virol ; 95(15): e0097120, 2021 07 12.
Article em En | MEDLINE | ID: mdl-34011540
HIV-1 encodes several accessory proteins-Nef, Vif, Vpr, and Vpu-whose functions are to modulate the cellular environment to favor immune evasion and viral replication. While Vpr was shown to mediate a G2/M cell cycle arrest and provide a replicative advantage during infection of myeloid cells, the mechanisms underlying these functions remain unclear. In this study, we defined HIV-1 Vpr proximity interaction network using the BioID proximity labeling approach and identified 352 potential Vpr partners/targets, including several complexes, such as the cell cycle-regulatory anaphase-promoting complex/cyclosome (APC/C). Herein, we demonstrate that both the wild type and cell cycle-defective mutants of Vpr induce the degradation of APC1, an essential APC/C scaffolding protein, and show that this activity relies on the recruitment of DCAF1 by Vpr and the presence of a functional proteasome. Vpr forms a complex with APC1, and the APC/C coactivators Cdh1 and Cdc20 are associated with these complexes. Interestingly, we found that Vpr encoded by the prototypic HIV-1 NL4.3 does not interact efficiently with APC1 and is unable to mediate its degradation as a result of a N28S-G41N amino acid substitution. In contrast, we show that APC1 degradation is a conserved feature of several primary Vpr variants from transmitted/founder virus. Functionally, Vpr-mediated APC1 degradation did not impact the ability of the protein to induce a G2 cell cycle arrest during infection of CD4+ T cells or enhance HIV-1 replication in macrophages, suggesting that this conserved activity may be important for other aspects of HIV-1 pathogenesis. IMPORTANCE The function of the Vpr accessory protein during HIV-1 infection remains poorly defined. Several cellular targets of Vpr were previously identified, but their individual degradation does not fully explain the ability of Vpr to impair the cell cycle or promote HIV-1 replication in macrophages. Here, we used the unbiased proximity labeling approach, called BioID, to further define the Vpr proximity interaction network and identified several potentially new Vpr partners/targets. We validated our approach by focusing on a cell cycle master regulator, the APC/C complex, and demonstrated that Vpr mediated the degradation of a critical scaffolding component of APC/C called APC1. Furthermore, we showed that targeting of APC/C by Vpr did not impact the known activity of Vpr. Since degradation of APC1 is a conserved feature of several primary variants of Vpr, it is likely that the interplay between Vpr and APC/C governs other aspects of HIV-1 pathogenesis.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Replicação Viral / Infecções por HIV / HIV-1 / Proteínas Serina-Treonina Quinases / Ubiquitina-Proteína Ligases / Produtos do Gene vpr do Vírus da Imunodeficiência Humana / Subunidade Apc1 do Ciclossomo-Complexo Promotor de Anáfase Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Replicação Viral / Infecções por HIV / HIV-1 / Proteínas Serina-Treonina Quinases / Ubiquitina-Proteína Ligases / Produtos do Gene vpr do Vírus da Imunodeficiência Humana / Subunidade Apc1 do Ciclossomo-Complexo Promotor de Anáfase Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article