title: Phylogenetically Distant Viruses Use the Same BH3-Only Protein Puma to Trigger Bax/Bak-Dependent Apoptosis of Infected Mouse and Human Cells.
abstract: Viruses can trigger apoptosis of infected host cells if not counteracted by cellular or viral anti-apoptotic proteins. These protective proteins either inhibit the activation of caspases or they act as Bcl-2 homologs to prevent Bax/Bak-mediated outer mitochondrial membrane permeabilization (MOMP). The exact mechanism by which viruses trigger MOMP has however remained enigmatic. Here we use two distinct types of viruses, a double stranded DNA virus, herpes simplex virus-1 (HSV-1) and a positive sense, single stranded RNA virus, Semliki Forest virus (SFV) to show that the BH3-only protein Puma is the major mediator of virus-induced Bax/Bak activation and MOMP induction. Indeed, when Puma was genetically deleted or downregulated by shRNA, mouse embryonic fibroblasts and IL-3-dependent monocytes as well as human colon carcinoma cells were as resistant to virus-induced apoptosis as their Bax/Bak double deficient counterparts (Bax/Bak-/-). Puma protein expression started to augment after 2 h postinfection with both viruses. Puma mRNA levels increased as well, but this occurred after apoptosis initiation (MOMP) because it was blocked in cells lacking Bax/Bak or overexpressing Bcl-xL. Moreover, none of the classical Puma transcription factors such as p53, p73 or p65 NFκB were involved in HSV-1-induced apoptosis. Our data suggest that viruses use a Puma protein-dependent mechanism to trigger MOMP and apoptosis in host cells.
authors.affiliation: Department of Biological and Environmental Sciences, University of Messina, Via F. Stagno d'Alcontres 31, I-98166, Messina, Italy; The Institute of Translational Pharmacology, CNR, Via Fosso del Cavaliere 100, I-00133, Rome, Italy; Institute of Molecular Medicine and Cell Research, Albert Ludwigs University of Freiburg, Stefan Meier Strasse 17, D-79104, Freiburg, Germany.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Papaianni
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert Ludwigs University of Freiburg, Stefan Meier Strasse 17, D-79104, Freiburg, Germany; Faculty of Biology, Albert Ludwigs University of Freiburg, Schänzlestrasse 1, D-79104, Freiburg, Germany.
authors.forename: Souhayla
authors.initials: S
authors.lastname: El Maadidi
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert Ludwigs University of Freiburg, Stefan Meier Strasse 17, D-79104, Freiburg, Germany; IMBS Program between Albert Ludwigs University of Freiburg, Freiburg, Germany, and University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schejtman
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert Ludwigs University of Freiburg, Stefan Meier Strasse 17, D-79104, Freiburg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Neumann
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert Ludwigs University of Freiburg, Stefan Meier Strasse 17, D-79104, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University of Freiburg, Albertstrasse 19a, D-79104, Freiburg, Germany; BIOSS, Centre for Biological Signaling Studies, Hebelstrasse 2, D-79104, Freiburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Maurer
authors.affiliation: Department of Biological and Environmental Sciences, University of Messina, Via F. Stagno d'Alcontres 31, I-98166, Messina, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Marino-Merlo
authors.affiliation: Department of Biological and Environmental Sciences, University of Messina, Via F. Stagno d'Alcontres 31, I-98166, Messina, Italy; The Institute of Translational Pharmacology, CNR, Via Fosso del Cavaliere 100, I-00133, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mastino
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert Ludwigs University of Freiburg, Stefan Meier Strasse 17, D-79104, Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University of Freiburg, Albertstrasse 19a, D-79104, Freiburg, Germany; BIOSS, Centre for Biological Signaling Studies, Hebelstrasse 2, D-79104, Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Borner
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D045325:HCT116 Cells; D018259:Herpesvirus 1, Human / Q000378:metabolism*; D006801:Humans; D051379:Mice; D028861:Nuclear Pore Complex Proteins; D010802:Phylogeny; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D012672:Semliki forest virus / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells; D014779:Virus Replication; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: C119724:AGFG1 protein, human; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D053222:Fas Ligand Protein; D028861:Nuclear Pore Complex Proteins; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D025521:Tumor Suppressor Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D053148:Caspase 3