title: Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation.
abstract: Oxidative tissue injury often accompanies viral infection, yet there is little understanding of how it influences virus replication. We show that multiple hepatitis C virus (HCV) genotypes are exquisitely sensitive to oxidative membrane damage, a property distinguishing them from other pathogenic RNA viruses. Lipid peroxidation, regulated in part through sphingosine kinase-2, severely restricts HCV replication in Huh-7 cells and primary human hepatoblasts. Endogenous oxidative membrane damage lowers the 50% effective concentration of direct-acting antivirals in vitro, suggesting critical regulation of the conformation of the NS3-4A protease and the NS5B polymerase, membrane-bound HCV replicase components. Resistance to lipid peroxidation maps genetically to transmembrane and membrane-proximal residues within these proteins and is essential for robust replication in cell culture, as exemplified by the atypical JFH1 strain of HCV. Thus, the typical, wild-type HCV replicase is uniquely regulated by lipid peroxidation, providing a mechanism for attenuating replication in stressed tissue and possibly facilitating long-term viral persistence.
authors: 1] Department of Medicine, Division of Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Daisuke
authors: D
authors: Yamane
authors: 1] Department of Medicine, Division of Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: David R
authors: DR
authors: McGivern
authors: 1] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Eliane
authors: E
authors: Wauthier
authors: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors: MinKyung
authors: M
authors: Yi
authors: Department of Pathology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Victoria J
authors: 0000000279097743
authors: VJ
authors: Madden
authors: Department of Internal Medicine I, J.W. Goethe University Hospital, Frankfurt, Germany.
authors: Christoph
authors: C
authors: Welsch
authors: Center for Integrated Protein Science Munich (CIPSM), Department of Life Sciences, Technical University Munich, Freising, Germany.
authors: Iris
authors: I
authors: Antes
authors: Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA.
authors: Yahong
authors: Y
authors: Wen
authors: 1] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Pauline E
authors: PE
authors: Chugh
authors: Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Charles E
authors: CE
authors: McGee
authors: Department of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Douglas G
authors: DG
authors: Widman
authors: Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Ichiro
authors: I
authors: Misumi
authors: 1] School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA. [2] Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA.
authors: Sibali
authors: S
authors: Bandyopadhyay
authors: 1] Department of Medicine, Division of Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [3] Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors: Seungtaek
authors: S
authors: Kim
authors: 1] Department of Medicine, Division of Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Tetsuro
authors: T
authors: Shimakami
authors: 1] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Tsunekazu
authors: T
authors: Oikawa
authors: 1] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [3] Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Jason K
authors: JK
authors: Whitmire
authors: 1] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Mark T
authors: MT
authors: Heise
authors: 1] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Dirk P
authors: DP
authors: Dittmer
authors: Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA.
authors: C Cheng
authors: CC
authors: Kao
authors: Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.
authors: Stuart M
authors: SM
authors: Pitson
authors: 1] School of Biology, Georgia Institute of Technology, Atlanta, Georgia, USA. [2] Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA.
authors: Alfred H
authors: AH
authors: Merrill
authors: 1] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Lola M
authors: LM
authors: Reid
authors: 1] Department of Medicine, Division of Infectious Diseases, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [2] Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. [3] Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors: Stanley M
authors: SM
authors: Lemon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000473:pathology; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy; D022781:Hepatocytes / Q000378:metabolism / Q000821:virology; D006801:Humans; D015227:Lipid Peroxidation; D018384:Oxidative Stress; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects*; D000099157:Sphingosine Kinase; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D012324:RNA-Dependent RNA Polymerase; D017361:Viral Nonstructural Proteins; D000099157:Sphingosine Kinase; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080106:NS4A protein, flavivirus; C466999:SPHKAP protein, human; C087036:NS-5 protein, hepatitis C virus