Abstract
Lipids are key components in the viral life cycle that affect host-pathogen interactions. In this study, we investigated the effect of HCV infection on sphingolipid metabolism, especially on endogenous SM levels, and the relationship between HCV replication and endogenous SM molecular species. We demonstrated that HCV induces the expression of the genes (SGMS1 and 2) encoding human SM synthases 1 and 2. We observed associated increases of both total and individual sphingolipid molecular species, as assessed in human hepatocytes and in the detergent-resistant membrane (DRM) fraction in which HCV replicates. SGMS1 expression had a correlation with HCV replication. Inhibition of sphingolipid biosynthesis with a hepatotropic serine palmitoyltransferase (SPT) inhibitor, NA808, suppressed HCV-RNA production while also interfering with sphingolipid metabolism. Further, we identified the SM molecular species that comprise the DRM fraction and demonstrated that these endogenous SM species interacted with HCV nonstructural 5B polymerase to enhance viral replication. Our results reveal that HCV alters sphingolipid metabolism to promote viral replication, providing new insights into the formation of the HCV replication complex and the involvement of host lipids in the HCV life cycle.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Enzymologic / drug effects
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Hepacivirus / physiology*
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Hepatitis C / genetics
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Hepatitis C / metabolism*
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Humans
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Membrane Proteins / biosynthesis
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Mice
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Nerve Tissue Proteins / biosynthesis
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Serine C-Palmitoyltransferase / antagonists & inhibitors
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Serine C-Palmitoyltransferase / genetics
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Serine C-Palmitoyltransferase / metabolism
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Sphingolipids / biosynthesis*
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Sphingolipids / genetics
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Transferases (Other Substituted Phosphate Groups) / biosynthesis
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Virus Replication / drug effects
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Virus Replication / physiology*
Substances
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Enzyme Inhibitors
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Membrane Proteins
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Nerve Tissue Proteins
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Sphingolipids
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Serine C-Palmitoyltransferase
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SGMS1 protein, human
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Transferases (Other Substituted Phosphate Groups)
Grants and funding
This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation of Japan; and the Ministry of Health, Labor, and Welfare of Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.