title: HIV-1 Vpr-induced apoptosis is cell cycle dependent and requires Bax but not ANT.
abstract: The HIV-1 accessory protein viral protein R (Vpr) causes G2 arrest and apoptosis in infected cells. We previously identified the DNA damage-signaling protein ATR as the cellular factor that mediates Vpr-induced G2 arrest and apoptosis. Here, we examine the mechanism of induction of apoptosis by Vpr and how it relates to induction of G2 arrest. We find that entry into G2 is a requirement for Vpr to induce apoptosis. We investigated the role of the mitochondrial permeability transition pore by knockdown of its essential component, the adenine nucleotide translocator. We found that Vpr-induced apoptosis was unaffected by knockdown of ANT. Instead, apoptosis is triggered through a different mitochondrial pore protein, Bax. In support of the idea that checkpoint activation and apoptosis induction are functionally linked, we show that Bax activation by Vpr was ablated when ATR or GADD45alpha was knocked down. Certain mutants of Vpr, such as R77Q and I74A, identified in long-term nonprogressors, have been proposed to inefficiently induce apoptosis while activating the G2 checkpoint in a normal manner. We tested the in vitro phenotypes of these mutants and found that their abilities to induce apoptosis and G2 arrest are indistinguishable from those of HIV-1NL4-3 vpr, providing additional support to the idea that G2 arrest and apoptosis induction are mechanistically linked.
authors.affiliation: Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Andersen
authors.forename: Jason L
authors.initials: JL
authors.lastname: DeHart
authors.forename: Erik S
authors.initials: ES
authors.lastname: Zimmerman
authors.forename: Orly
authors.initials: O
authors.lastname: Ardon
authors.forename: Baek
authors.initials: B
authors.lastname: Kim
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jacquot
authors.forename: Serge
authors.initials: S
authors.lastname: Benichou
authors.forename: Vicente
authors.initials: V
authors.lastname: Planelles
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D020169:Caspases / Q000502:physiology; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D016195:G2 Phase / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D016336:Gene Products, vpr / Q000235:genetics / Q000502:physiology*; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000502:physiology*; D054325:vpr Gene Products, Human Immunodeficiency Virus; D000097642:GADD45 Proteins
chemical_list: D033741:Adenine Nucleotide Translocator 1; D051017:Apoptosis Regulatory Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D020169:Caspases; D018797:Cell Cycle Proteins; D016336:Gene Products, vpr; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009153:Mutagens; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D051028:bcl-2-Associated X Protein; D054325:vpr Gene Products, Human Immunodeficiency Virus; C412403:DIABLO protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C576597:ATR protein, human