title: A novel mitochondrial MAVS/Caspase-8 platform links RNA virus-induced innate antiviral signaling to Bax/Bak-independent apoptosis.
abstract: Semliki Forest virus (SFV) requires RNA replication and Bax/Bak for efficient apoptosis induction. However, cells lacking Bax/Bak continue to die in a caspase-dependent manner. In this study, we show in both mouse and human cells that this Bax/Bak-independent pathway involves dsRNA-induced innate immune signaling via mitochondrial antiviral signaling (MAVS) and caspase-8. Bax/Bak-deficient or Bcl-2- or Bcl-xL-overexpressing cells lacking MAVS or caspase-8 expression are resistant to SFV-induced apoptosis. The signaling pathway triggered by SFV does neither involve death receptors nor the classical MAVS effectors TNFR-associated factor-2, IRF-3/7, or IFN-β but the physical interaction of MAVS with caspase-8 on mitochondria in a FADD-independent manner. Consistently, caspase-8 and -3 activation are reduced in MAVS-deficient cells. Thus, after RNA virus infection MAVS does not only elicit a type I antiviral response but also recruits caspase-8 to mitochondria to mediate caspase-3 activation and apoptosis in a Bax/Bak-independent manner.
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert Ludwigs University Freiburg, D-79104 Freiburg, Germany;
authors.forename: Souhayla
authors.initials: S
authors.lastname: El Maadidi
authors.forename: Laura
authors.initials: L
authors.lastname: Faletti
authors.forename: Birgit
authors.initials: B
authors.lastname: Berg
authors.forename: Christin
authors.initials: C
authors.lastname: Wenzl
authors.forename: Katrin
authors.initials: K
authors.lastname: Wieland
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
authors.forename: Ulrich
authors.initials: U
authors.lastname: Maurer
authors.forename: Christoph
authors.initials: C
authors.lastname: Borner
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000502:physiology*; D003588:Cytopathogenic Effect, Viral / Q000502:physiology*; D053487:DEAD-box RNA Helicases / Q000502:physiology; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein / Q000502:physiology; D005347:Fibroblasts / Q000821:virology; D057809:HEK293 Cells / Q000821:virology; D006367:HeLa Cells / Q000821:virology; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D012367:RNA, Viral / Q000235:genetics; D012672:Semliki forest virus / Q000502:physiology*; D015398:Signal Transduction; D014779:Virus Replication; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053148:Caspase 3; D053181:Caspase 8; D053487:DEAD-box RNA Helicases; D053200:Fas-Associated Death Domain Protein; D000072640:Interferon-Induced Helicase, IFIH1; D019253:Proto-Oncogene Proteins c-bcl-2; D012367:RNA, Viral; D051020:bcl-X Protein; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; C505533:FADD protein, human; C505534:Fadd protein, mouse; C512612:MAVS protein, mouse; C505371:MAVS protein, human; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C452815:IFIH1 protein, human; C510592:Ifih1 protein, mouse