title: Cytosolic DNA triggers mitochondrial apoptosis via DNA damage signaling proteins independently of AIM2 and RNA polymerase III.
abstract: A key host response to limit microbial spread is the induction of cell death when foreign nucleic acids are sensed within infected cells. In mouse macrophages, transfected DNA or infection with modified vaccinia virus Ankara (MVA) can trigger cell death via the absent in melanoma 2 (AIM2) inflammasome. In this article, we show that nonmyeloid human cell types lacking a functional AIM2 inflammasome still die in response to cytosolic delivery of different DNAs or infection with MVA. This cell death induced by foreign DNA is independent of caspase-8 and carries features of mitochondrial apoptosis: dependence on BAX, APAF-1, and caspase-9. Although it does not require the IFN pathway known to be triggered by infection with MVA or transfected DNA via polymerase III and retinoid acid-induced gene I-like helicases, it shows a strong dependence on components of the DNA damage signaling pathway: cytosolic delivery of DNA or infection with MVA leads to phosphorylation of p53 (serines 15 and 46) and autophosphorylation of ataxia telangiectasia mutated (ATM); depleting p53 or ATM with small interfering RNA or inhibiting the ATM/ATM-related kinase family by caffeine strongly reduces apoptosis. Taken together, our findings suggest that a pathway activating DNA damage signaling plays an important independent role in detecting intracellular foreign DNA, thereby complementing the induction of IFN and activation of the AIM2 inflammasome.
authors.affiliation: Department of Medicine, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wenzel
authors.forename: Michael
authors.initials: M
authors.lastname: Wunderlich
authors.forename: Robert
authors.initials: R
authors.lastname: Besch
authors.forename: Hendrik
authors.initials: H
authors.lastname: Poeck
authors.forename: Simone
authors.initials: S
authors.lastname: Willms
authors.forename: Astrid
authors.initials: A
authors.lastname: Schwantes
authors.forename: Melanie
authors.initials: M
authors.lastname: Kremer
authors.forename: Gerd
authors.initials: G
authors.lastname: Sutter
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Andreas
authors.initials: A
authors.lastname: Schmidt
authors.forename: Simon
authors.initials: S
authors.lastname: Rothenfusser
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003600:Cytosol; D004249:DNA Damage / Q000276:immunology*; D004279:DNA, Viral / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007372:Interferons / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012320:RNA Polymerase III / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014615:Vaccinia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C410167:AIM2 protein, human; C506592:APAF1 protein, human; C540422:Aim2 protein, mouse; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; C494826:BAX protein, human; C494827:Bax protein, mouse; D018797:Cell Cycle Proteins; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D009687:Nuclear Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D007372:Interferons; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D012320:RNA Polymerase III; C505526:Casp8 protein, mouse; D053181:Caspase 8