ArticleNature medicine2014
Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation.
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Article in Nature medicine, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 91 papers.
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91citing papers in PubMed
9.7field-weighted citation impact, top 1% of its field
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Who cites it
91 citing papers in PubMed, 154 citations in OpenAlex.
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- Phospholipid-driven conformational switching of HCV NS5A links protein folding to replication membrane remodeling.Science advances · 2026Article
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- Heat shock protein 90 chaperone activity is required for hepatitis A virus replication.Journal of virology · 2025Article
- Defence Warriors: Exploring the crosstalk between polyamines and oxidative stress during microbial pathogenesis.Redox biology · 2025Review
- Impaired ApoB secretion triggers enhanced secretion of ApoE to maintain triglyceride homeostasis in hepatoma cells.Journal of lipid research · 2025Article
- Thio-ProTide strategy: A novel HActa pharmaceutica Sinica. B · 2024Article
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- Ironing out the role of ferroptosis in immunity.Immunity · 2024Review
- Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Viral Hepatitis: The Interlink.Pathogens (Basel, Switzerland) · 2024Review
- Binding of microRNA-122 to the hepatitis C virus 5' untranslated region modifies interactions with poly(C) binding protein 2 and the NS5B viral polymerase.Nucleic acids research · 2023Article
- Zika virus remodelled ER membranes contain proviral factors involved in redox and methylation pathways.Nature communications · 2023Article
- Hepatoviruses promote very-long-chain fatty acid and sphingolipid synthesis for viral RNA replication and quasi-enveloped virus release.Science advances · 2023Article
- Article
31 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
24 authors at 7 institutions in 3 countries.
Daisuke Yamane1] 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.
David R McGivern1] 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.
Eliane Wauthier1] 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.
MinKyung YiDepartment of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
Victoria J MaddenDepartment of Pathology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.ORCID 0000000279097743
Christoph WelschDepartment of Internal Medicine I, J.W. Goethe University Hospital, Frankfurt, Germany.
Iris AntesCenter for Integrated Protein Science Munich (CIPSM), Department of Life Sciences, Technical University Munich, Freising, Germany.
Yahong WenDepartment of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA.
Pauline E Chugh1] 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.
Charles E McGeeDepartment of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Douglas G WidmanDepartment of Epidemiology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Ichiro MisumiDepartment of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Sibali Bandyopadhyay1] 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.
Seungtaek Kim1] 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.
Tetsuro Shimakami1] 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.
Tsunekazu Oikawa1] 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.
Jason K Whitmire1] 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.
Mark T Heise1] 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.
Dirk P Dittmer1] 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.
C Cheng KaoDepartment of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA.
Stuart M PitsonCentre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia.
Alfred H Merrill1] 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.
Lola M Reid1] 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.
Stanley M Lemon1] 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.
University of North Carolina at Chapel Hill · USGeorgia Institute of Technology · USIndiana University Bloomington · USCenter for Integrated Protein Science Munich · DEGoethe University Frankfurt · DESouth Australia Pathology · AUThe University of Texas Medical Branch at Galveston · US
Funding
Virology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Deborah F. Tate · 1985 to 2026
$201.5MVirology, Immunology, and Microbiology CoreP30AI050410 · NIAID · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DAVID M. MARGOLIS · 2001 to 2026
$76.9MSTEROL LIPIDSU54GM069338 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI DENNIS, EDWARD A · 2003 to 2013
$72.2MPILOT AND FEASIBILITY STUDIESP30DK034987 · NIDDK · UNIV OF NORTH CAROLINA CHAPEL HILL · PI ROBERT S. SANDLER · 1985 to 2026
$30.5MProteomics Pathway DiscoveryU19AI109965 · NIAID · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DUNCAN, JOSEPH A · 2014 to 2018
$14.9MART Modulation of Viral Pathogenesis in Oral EpitheliaR01DE018304 · NIDCR · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DITTMER, DIRK P · 2007 to 2025
$6.9MMembrane Hijacking: Biogenesis and Fate of Quasi-Enveloped HepatovirusR01AI103083 · NIAID · UNIV OF NORTH CAROLINA CHAPEL HILL · PI LEMON, STANLEY M. · 2012 to 2021
$4.0MMicro-RNA 122 and Chronic Hepatitis CR01AI095690 · NIAID · UNIV OF NORTH CAROLINA CHAPEL HILL · PI LEMON, STANLEY M. · 2011 to 2020
$3.7MMurine Model of HCV-Associated Human Liver CancerR01CA164029 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI LEMON, STANLEY M., SU, LISHAN · 2012 to 2016
$2.3MFunction of NS2 in Hepatitis C Virus Assembly and ReleaseR01AI075090 · NIAID · UNIVERSITY OF TEXAS MED BR GALVESTON · PI YI, MINKYUNG · 2008 to 2012
$1.6MRNA-dependent RNA Synthesis by the Hepatitis C VirusR01AI073335 · NIAID · TRUSTEES OF INDIANA UNIVERSITY · PI KAO, CHENG C · 2008 to 2012
$1.5MUK SPORE in Gastrointestinal CancerP20CA150343 · NCI · UNIVERSITY OF KENTUCKY · PI EVERS, BERNARD MARK · 2009 to 2011
$1.5MNCI NIH HHS P20 CA150343NCI NIH HHS P30 CA016086NCI NIH HHS P30-CA016086NCI NIH HHS R01 CA164029NCI NIH HHS R01-CA164029NCI NIH HHS R21-CA182322NIAID NIH HHS F32-AI094941NIAID NIH HHS P30 AI050410NIAID NIH HHS R01 AI073335NIAID NIH HHS R01-AI073335NIAID NIH HHS R01 AI075090NIAID NIH HHS R01-AI075090NIAID NIH HHS R01 AI095690NIAID NIH HHS R01-AI095690NIAID NIH HHS R01 AI103083NIAID NIH HHS U19 AI109965NIAID NIH HHS U19-AI109965NIDCR NIH HHS R01 DE018304NIDCR NIH HHS R01-DE018304NIDDK NIH HHS P30 DK034987NIGMS NIH HHS U54 GM069338NIGMS NIH HHS U54-GM069338
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.
Indexed as
Lipid PeroxidationOxidative StressAdaptor Proteins, Signal TransducingAntiviral AgentsCell LineCell MembraneDEAD-box RNA HelicasesHepacivirusHepatitis CHepatocytesHumansNucleoside-TriphosphatasePhosphotransferases (Alcohol Group Acceptor)RNA-Dependent RNA PolymeraseRNA InterferenceRNA, Small InterferingAdaptor Proteins, Signal TransducingAntiviral AgentsDEAD-box RNA HelicasesNS3 protein, hepatitis C virusNS4A protein, flavivirusNS-5 protein, hepatitis C virusNucleoside-TriphosphatasePhosphotransferases (Alcohol Group Acceptor)RNA-Dependent RNA PolymeraseRNA, Small InterferingSerine EndopeptidasesSphingosine KinaseSPHKAP protein, humanViral Nonstructural ProteinsViral Proteases
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