title: Casp8p41 generated by HIV protease kills CD4 T cells through direct Bak activation.
abstract: Previous studies have shown that human immunodeficiency virus (HIV) protease cleaves procaspase 8 to a fragment, termed Casp8p41, that lacks caspase activity but nonetheless contributes to T cell apoptosis. Herein, we show that Casp8p41 contains a domain that interacts with the BH3-binding groove of pro-apoptotic Bak to cause Bak oligomerization, Bak-mediated membrane permeabilization, and cell death. Levels of active Bak are higher in HIV-infected T cells that express Casp8p41. Conversely, targeted mutations in the Bak-interacting domain diminish Bak binding and Casp8p41-mediated cell death. Similar mutations in procaspase 8 impair the ability of HIV to kill infected T cells. These observations support a novel paradigm in which HIV converts a normal cellular constituent into a direct activator that functions like a BH3-only protein.
authors.affiliation: Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294 Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Sainski
authors.affiliation: Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294.
authors.forename: Haiming
authors.initials: H
authors.lastname: Dai
authors.affiliation: Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294.
authors.forename: Sekar
authors.initials: S
authors.lastname: Natesampillai
authors.affiliation: Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294.
authors.forename: Yuan-Ping
authors.initials: YP
authors.lastname: Pang
authors.affiliation: Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bren
authors.affiliation: Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Cummins
authors.affiliation: Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294.
authors.forename: Cristina
authors.initials: C
authors.lastname: Correia
authors.affiliation: Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294 Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294.
authors.forename: X Wei
authors.initials: XW
authors.lastname: Meng
authors.affiliation: Department of Biochemistry and Molecular Biology and Department of Molecular Medicine, Mayo Clinic, Rochester MN 55905.
authors.forename: James E
authors.initials: JE
authors.lastname: Tarara
authors.affiliation: Department of Biochemistry and Molecular Biology and Department of Molecular Medicine, Mayo Clinic, Rochester MN 55905.
authors.forename: Marina
authors.initials: M
authors.lastname: Ramirez-Alvarado
authors.affiliation: Department of Biochemistry and Molecular Biology and Department of Molecular Medicine, Mayo Clinic, Rochester MN 55905.
authors.forename: David J
authors.initials: DJ
authors.lastname: Katzmann
authors.affiliation: Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294.
authors.forename: Christina
authors.initials: C
authors.lastname: Ochsenbauer
authors.affiliation: Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294.
authors.forename: John C
authors.initials: JC
authors.lastname: Kappes
authors.affiliation: Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294 Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294 Kaufmann.Scott@Mayo.edu Badley.Andrew@Mayo.edu.
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.affiliation: Department of Molecular Pharmacology and Experiment Therapeutics, Division of Oncology Research, Division of Infectious Diseases, and Department of Medicine, University of Alabama, Birmingham, AL 35294 Department of Biochemistry and Molecular Biology and Department of Molecular Medicine, Mayo Clinic, Rochester MN 55905 Kaufmann.Scott@Mayo.edu Badley.Andrew@Mayo.edu.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Badley
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology* / Q000821:virology; D053181:Caspase 8 / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D016333:HIV Protease / Q000502:physiology*; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D059748:Proteolysis; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry / Q000378:metabolism*
chemical_list: C494772:BAK1 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; C505530:CASP8 protein, human; D053181:Caspase 8; D016333:HIV Protease