Abstract
Background:
Host responses to viral infection include both immune activation and programmed cell death. The mitochondrial antiviral signaling adaptor, MAVS (IPS-1, VISA or Cardif) is critical for host defenses to viral infection by inducing type-1 interferons (IFN-I), however its role in virus-induced apoptotic responses has not been elucidated.
Principal findings:
We show that MAVS causes apoptosis independent of its function in initiating IFN-I production. MAVS-induced cell death requires mitochondrial localization, is caspase dependent, and displays hallmarks of apoptosis. Furthermore, MAVS(-/-) fibroblasts are resistant to Sendai virus-induced apoptosis. A functional screen identifies the hepatitis C virus NS3/4A and the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) nonstructural protein (NSP15) as inhibitors of MAVS-induced apoptosis, possibly as a method of immune evasion.
Significance:
This study describes a novel role for MAVS in controlling viral infections through the induction of apoptosis, and identifies viral proteins which inhibit this host response.
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / physiology*
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Animals
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Apoptosis / immunology
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Apoptosis / physiology*
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Base Sequence
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Caspases / metabolism
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Cell Line
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Cells, Cultured
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Endoribonucleases
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Host-Pathogen Interactions / immunology
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Host-Pathogen Interactions / physiology*
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Humans
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Interferon Regulatory Factor-3 / antagonists & inhibitors
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Interferon Regulatory Factor-3 / genetics
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Interferon Type I / biosynthesis
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Mice
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Mice, Knockout
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Mitochondria / metabolism
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Models, Biological
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NF-kappa B / metabolism
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Protein Structure, Tertiary
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RNA, Small Interfering / genetics
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RNA-Dependent RNA Polymerase / physiology
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Sendai virus / pathogenicity
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Viral Nonstructural Proteins / physiology
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Viral Proteins / physiology*
Substances
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Adaptor Proteins, Signal Transducing
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IPS-1 protein, mouse
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Interferon Type I
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MAVS protein, human
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NF-kappa B
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RNA, Small Interfering
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Viral Nonstructural Proteins
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Viral Proteins
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RNA-Dependent RNA Polymerase
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Endoribonucleases
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nidoviral uridylate-specific endoribonuclease
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Caspases