Viral and therapeutic control of IFN-beta promoter stimulator 1 during hepatitis C virus infection.
Viral signaling through retinoic acid-inducible gene-I (RIG-I) and its adaptor protein, IFN promoter-stimulator 1 (IPS-1), activates IFN regulatory factor-3 (IRF-3) and the host IFN-alpha/beta response that limits virus infection. The hepatitis C virus (HCV) NS3/4A protease cleaves IPS-1 to block RIG-I signaling, but how this regulation controls the host response to HCV is not known. Moreover, endogenous IPS-1 cleavage has not been demonstrated in the context of HCV infection in vitro or in vivo. Here, we show that HCV infection transiently induces RIG-I- and IPS-1-dependent IRF-3 activation. This host response limits HCV production and constrains cellular permissiveness to infection. However, HCV disrupts this response early in infection by NS3/4A cleavage of IPS-1 at C508, releasing IPS-1 from the mitochondrial membrane. Cleavage results in subcellular redistribution of IPS-1 and loss of interaction with RIG-I, thereby preventing downstream activation of IRF-3 and IFN-beta induction. Liver tissues from chronically infected patients similarly demonstrate subcellular redistribution of IPS-1 in infected hepatocytes and IPS-1 cleavage associated with a lack of ISG15 expression and conjugation of target proteins in vivo. Importantly, small-molecule inhibitors of NS3/4A prevent cleavage and restore RIG-I signaling of IFN-beta induction. Our results suggest a dynamic model in which early activation of IRF-3 and induction of antiviral genes are reversed by IPS-1 proteolysis and abrogation of RIG-I signaling as NS3/4A accumulates in newly infected cells. HCV protease inhibitors effectively prevent IPS-1 proteolysis, suggesting they may be capable of restoring this innate host response in clinical practice.
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Yueh-Ming
YM
Loo
David M
DM
Owen
Kui
K
Li
Andrea K
AK
Erickson
Cynthia L
CL
Johnson
Penny M
PM
Fish
D Spencer
DS
Carney
Ting
T
Wang
Hisashi
H
Ishida
Mitsutoshi
M
Yoneyama
Takashi
T
Fujita
Takeshi
T
Saito
William M
WM
Lee
Curt H
CH
Hagedorn
Daryl T-Y
DT
Lau
Steven A
SA
Weinman
Stanley M
SM
Lemon
Michael
M
Gale
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D014644:Genetic Variation; D016174:Hepacivirus / Q000235:genetics; D006526:Hepatitis C / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics*; D008113:Liver Neoplasms; D008928:Mitochondria / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; C505371:MAVS protein, human