GB virus B disrupts RIG-I signaling by NS3/4A-mediated cleavage of the adaptor protein MAVS.
Understanding the mechanisms of hepatitis C virus (HCV) pathogenesis and persistence has been hampered by the lack of small, convenient animal models. GB virus B (GBV-B) is phylogenetically the closest related virus to HCV. It causes generally acute and occasionally chronic hepatitis in small primates and is used as a surrogate model for HCV. It is not known, however, whether GBV-B has evolved strategies to circumvent host innate defenses similar to those of HCV, a property that may contribute to HCV persistence in vivo. We show here in cultured tamarin hepatocytes that GBV-B NS3/4A protease, but not a related catalytically inactive mutant, effectively blocks innate intracellular antiviral responses signaled through the RNA helicase, retinoic acid-inducible gene I (RIG-I), an essential sensor molecule that initiates host defenses against many RNA viruses, including HCV. GBV-B NS3/4A protease specifically cleaves mitochondrial antiviral signaling protein (MAVS; also known as IPS-1/Cardif/VISA) and dislodges it from mitochondria, thereby disrupting its function as a RIG-I adaptor and blocking downstream activation of both interferon regulatory factor 3 and nuclear factor kappa B. MAVS cleavage and abrogation of virus-induced interferon responses were also observed in Huh7 cells supporting autonomous replication of subgenomic GBV-B RNAs. Our data indicate that, as in the case of HCV, GBV-B has evolved to utilize its major protease to disrupt RIG-I signaling and impede innate antiviral defenses. These data provide further support for the use of GBV-B infection in small primates as an accurate surrogate model for deciphering virus-host interactions in hepacivirus pathogenesis.
Chen
Zihong
Z
Department of Microbiology & Immunology, Center for Hepatitis Research, Institute for Human Infections & Immunity, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1019, USA.
Benureau
Yann
Y
Rijnbrand
Rene
R
Yi
Jianzhong
J
Wang
Ting
T
Warter
Lucile
L
Lanford
Robert E
RE
Weinman
Steven A
SA
Lemon
Stanley M
SM
Martin
Annette
A
Li
Kui
K
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D029406:GB virus B / Q000472:pathogenicity*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D022781:Hepatocytes / Q000821:virology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D021382:Protein Sorting Signals; D020365:RNA Helicases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D021382:Protein Sorting Signals; D020365:RNA Helicases; D018168:Receptors, Retinoic Acid; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C494232:IRF3 protein, human; C505371:MAVS protein, human; C060028:NS3 protein, flavivirus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C437968:PLAAT4 protein, human