title: Anti-apoptotic Bcl-XL but not Mcl-1 contributes to protection against virus-induced apoptosis.
abstract: Infection of mammalian cells with viruses often induces apoptosis. How the recognition of viruses leads to apoptosis of the infected cell and which host cell factors regulate this cell death is incompletely understood. In this study, we focussed on two major anti-apoptotic proteins of the host cell, whose abundance and activity are important for cell survival, the Bcl-2-like proteins Mcl-1 and Bcl-XL. During infection of epithelial cells and fibroblasts with modified vaccinia virus Ankara (MVA), Mcl-1 protein levels dropped but the MVA Bcl-2-like protein F1L could replace Mcl-1 functionally; a similar activity was found in vaccinia virus (VACV)-infected cells. During infection with murine cytomegalovirus (MCMV), Mcl-1-levels were not reduced but a viral Mcl-1-like activity was also generated. Infection of mouse macrophages with any of these viruses, on the other hand, induced apoptosis. Virus-induced macrophage apoptosis was unaltered in the absence of Mcl-1. However, apoptosis was substantially increased in infected Bcl-XL-deficient macrophages or macrophages treated with the Bcl-2/Bcl-XL-inhibitor ABT-737. Genetic loss of Bcl-XL or treatment of macrophages with ABT-737 reduced the generation of infectious VACV. These data show that Mcl-1 is dispensable for the regulation of apoptosis during infection with different large DNA viruses, either because the viruses replace its function (in fibroblasts and epithelial cells) or because the pro-apoptotic activity generated by the infection appears not to be blocked by it (in macrophages). Bcl-XL, on the other hand, can be important to maintain survival of virus-infected cells, and its activity can determine outcome of the infection.
authors.affiliation: Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Ohmer
authors.affiliation: Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Arnim
authors.initials: A
authors.lastname: Weber
authors.affiliation: Institute for Infectious Diseases and Zoonoses, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Sutter
authors.affiliation: Institute of Virology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Ehrhardt
authors.affiliation: Institute for Virology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Zimmermann
authors.affiliation: Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Häcker
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000821:virology; D005347:Fibroblasts / Q000187:drug effects / Q000821:virology; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000821:virology; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D014616:Vaccinia virus / Q000502:physiology*; D014771:Virion / Q000187:drug effects / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism*
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D051020:bcl-X Protein