MAVS-mediated apoptosis and its inhibition by viral proteins.
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.


RESULTS
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.


CONCLUSIONS
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.
Lei
Yu
Y
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Moore
Chris B
CB
Liesman
Rachael M
RM
O'Connor
Brian P
BP
Bergstralh
Daniel T
DT
Chen
Zhijian J
ZJ
Pickles
Raymond J
RJ
Ting
Jenny P-Y
JP
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D001483:Base Sequence; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004722:Endoribonucleases; D054884:Host-Pathogen Interactions / Q000276:immunology / Q000502:physiology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000235:genetics; D007370:Interferon Type I / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase / Q000502:physiology; D029082:Sendai virus / Q000472:pathogenicity; D017361:Viral Nonstructural Proteins / Q000502:physiology; D014764:Viral Proteins / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D020169:Caspases; D004722:Endoribonucleases; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D016328:NF-kappa B; D034741:RNA, Small Interfering; D012324:RNA-Dependent RNA Polymerase; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C512612:MAVS protein, mouse; C494232:IRF3 protein, human; C505371:MAVS protein, human; C000657925:nidoviral uridylate-specific endoribonuclease