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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / physiology*
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Animals
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Apoptosis / physiology*
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Caspase 3 / metabolism
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Caspase 8 / physiology*
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Cytopathogenic Effect, Viral / physiology*
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DEAD-box RNA Helicases / physiology
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Enzyme Activation
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Fas-Associated Death Domain Protein / physiology
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Fibroblasts / virology
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HEK293 Cells / virology
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HeLa Cells / virology
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Humans
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Interferon-Induced Helicase, IFIH1
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Mice
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Mitochondria / enzymology
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Mitochondria / physiology*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA Interference
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RNA, Viral / genetics
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Semliki forest virus / physiology*
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Signal Transduction
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Virus Replication
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bcl-X Protein / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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BCL2L1 protein, human
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Bcl2l1 protein, mouse
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FADD protein, human
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Fadd protein, mouse
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Fas-Associated Death Domain Protein
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IPS-1 protein, mouse
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MAVS protein, human
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Proto-Oncogene Proteins c-bcl-2
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RNA, Viral
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bcl-X Protein
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CASP3 protein, human
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CASP8 protein, human
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Casp3 protein, mouse
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Casp8 protein, mouse
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Caspase 3
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Caspase 8
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IFIH1 protein, human
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Ifih1 protein, mouse
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DEAD-box RNA Helicases
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Interferon-Induced Helicase, IFIH1