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 KaoStuart M. Pitson, Alfred H. Merrill, Lola M. Reid, Stanley M. Lemon

Research output: Contribution to journalArticle

85 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Yamane, D., McGivern, D. R., Wauthier, E., Yi, M., Madden, V. J., Welsch, C., Antes, I., Wen, Y., Chugh, P. E., McGee, C. E., Widman, D. G., Misumi, I., Bandyopadhyay, S., Kim, S., Shimakami, T., Oikawa, T., Whitmire, J. K., Heise, M. T., Dittmer, D. P., ... 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