Phylogenetically Distant Viruses Use the Same BH3-Only Protein Puma to Trigger Bax/Bak-Dependent Apoptosis of Infected Mouse and Human Cells

• Published in: PloS one 2015-06, Vol.10 (6), p.e0126645-e0126645
• Main Authors: Papaianni, Emanuela, El Maadidi, Souhayla, Schejtman, Andrea, Neumann, Simon, Maurer, Ulrich, Marino-Merlo, Francesca, Mastino, Antonio, Borner, Christoph
• Format: Article
• Language: English
• Subjects: Activation; Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; BAK protein; Bax protein; bcl-2 Homologous Antagonist-Killer Protein - metabolism; Bcl-2 protein; bcl-2-Associated X Protein - metabolism; Bcl-x protein; Biology; Caspase 3 - metabolism; Colon; Cytochromes c - metabolism; Cytokines; Deoxyribonucleic acid; DNA; DNA viruses; Embryo fibroblasts; Embryos; Environmental science; Enzyme Activation; Fas Ligand Protein - metabolism; Fibroblasts; Fibroblasts - metabolism; HCT116 Cells; Herpes simplex; Herpes viruses; Herpesvirus 1, Human - metabolism; Homology; Humans; Infections; Interleukin 3; Kinases; Major outer membrane protein; Medicine; Mice; Mitochondria; Monocytes; NF-κB protein; Nuclear Pore Complex Proteins; p53 Protein; Pathogens; Phylogeny; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Ribonucleic acid; RNA; RNA viruses; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA-Binding Proteins; Semliki forest virus - metabolism; TNF-Related Apoptosis-Inducing Ligand - metabolism; Transcription factors; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; U937 Cells; Virus Replication; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0126645

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.