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

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 & 4 others Stuart M. Pitson, Alfred H. Merrill, Lola M. Reid, Stanley M. Lemon

Research output: Contribution to journalArticle

78 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)927-935
Number of pages9
JournalNature Medicine
Volume20
Issue number8
DOIs
StatePublished - 2014

Fingerprint

RNA Replicase
Viruses
Hepacivirus
Lipid Peroxidation
Lipids
Membranes
Virus Replication
Viral Structures
RNA Viruses
Virus Diseases
Tissue
Antiviral Agents
Peptide Hydrolases
Cell Culture Techniques
Genotype
Cell culture
Conformations
Wounds and Injuries
RNA
Proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Yamane, D., McGivern, D. R., Wauthier, E., Yi, M., Madden, V. J., Welsch, C., ... Lemon, S. M. (2014). Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation. Nature Medicine, 20(8), 927-935. https://doi.org/10.1038/nm.3610

Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation. / Yamane, Daisuke; McGivern, David R.; Wauthier, Eliane; Yi, Minkyung; Madden, Victoria J.; Welsch, Christoph; Antes, Iris; Wen, Yahong; Chugh, Pauline E.; McGee, Charles E.; Widman, Douglas G.; Misumi, Ichiro; Bandyopadhyay, Sibali; Kim, Seungtaek; Shimakami, Tetsuro; Oikawa, Tsunekazu; Whitmire, Jason K.; Heise, Mark T.; Dittmer, Dirk P.; Kao, C. Cheng; Pitson, Stuart M.; Merrill, Alfred H.; Reid, Lola M.; Lemon, Stanley M.

In: Nature Medicine, Vol. 20, No. 8, 2014, p. 927-935.

Research output: Contribution to journalArticle

Yamane, D, McGivern, DR, Wauthier, E, Yi, M, Madden, VJ, Welsch, C, Antes, I, Wen, Y, Chugh, PE, McGee, CE, Widman, DG, Misumi, I, Bandyopadhyay, S, Kim, S, Shimakami, T, Oikawa, T, Whitmire, JK, Heise, MT, Dittmer, DP, Kao, CC, Pitson, SM, Merrill, AH, Reid, LM & Lemon, SM 2014, 'Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation', Nature Medicine, vol. 20, no. 8, pp. 927-935. https://doi.org/10.1038/nm.3610
Yamane, Daisuke ; McGivern, David R. ; Wauthier, Eliane ; Yi, Minkyung ; Madden, Victoria J. ; Welsch, Christoph ; Antes, Iris ; Wen, Yahong ; Chugh, Pauline E. ; McGee, Charles E. ; Widman, Douglas G. ; Misumi, Ichiro ; Bandyopadhyay, Sibali ; Kim, Seungtaek ; Shimakami, Tetsuro ; Oikawa, Tsunekazu ; Whitmire, Jason K. ; Heise, Mark T. ; Dittmer, Dirk P. ; Kao, C. Cheng ; Pitson, Stuart M. ; Merrill, Alfred H. ; Reid, Lola M. ; Lemon, Stanley M. / Regulation of the hepatitis C virus RNA replicase by endogenous lipid peroxidation. In: Nature Medicine. 2014 ; Vol. 20, No. 8. pp. 927-935.
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