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Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation

Authors
 Daisuke Yamane  ;  David R McGivern  ;  Eliane Wauthier  ;  MinKyung Yi  ;  Victoria J Madden  ;  Christoph Welsch  ;  Iris Antes  ;  Yahong Wen  ;  Pauline E Chugh  ;  Charles E McGee  ;  Douglas G Widman  ;  Ichiro Misumi  ;  Sibali Bandyopadhyay  ;  Seungtaek Kim  ;  Tetsuro Shimakami  ;  Tsunekazu Oikawa  ;  Jason K Whitmire  ;  Mark T Heise  ;  Dirk P Dittmer  ;  C Cheng Kao  ;  Stuart M Pitson  ;  Alfred H Merrill Jr  ;  Lola M Reid  ;  Stanley M Lemon 
Citation
 NATURE MEDICINE, Vol.20(8) : 927-935, 2014 
Journal Title
NATURE MEDICINE
ISSN
 1078-8956 
Issue Date
2014
MeSH
Adaptor Proteins, Signal Transducing/genetics ; Antiviral Agents/pharmacology ; Cell Line ; Cell Membrane/pathology ; Hepacivirus/drug effects ; Hepacivirus/enzymology* ; Hepacivirus/genetics ; Hepatitis C/drug therapy ; Hepatocytes/metabolism ; Hepatocytes/virology ; Humans ; Lipid Peroxidation* ; Oxidative Stress* ; Phosphotransferases (Alcohol Group Acceptor)/genetics ; Phosphotransferases (Alcohol Group Acceptor)/metabolism ; RNA Interference ; RNA Replicase/metabolism* ; RNA, Small Interfering/genetics ; Viral Nonstructural Proteins/genetics ; Viral Nonstructural Proteins/metabolism* ; Virus Replication/drug effects*
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.
Full Text
http://www.nature.com/nm/journal/v20/n8/full/nm.3610.html
DOI
10.1038/nm.3610
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Seung Taek(김승택)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/99500
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