Self-Enhancement of Hepatitis C Virus Replication by Promotion of Specific Sphingolipid Biosynthesis

Yuichi Hirata, Kazutaka Ikeda, Masayuki Sudoh, Yuko Tokunaga, Akemi Suzuki, Leiyun Weng, Masatoshi Ohta, Yoshimi Tobita, Ken Okano, Kazuhisa Ozeki, Kenichi Kawasaki, Takuo Tsukuda, Asao Katsume, Yuko Aoki, Takuya Umehara, Satoshi Sekiguchi, Tetsuya Toyoda, Kunitada Shimotohno, Tomoyoshi Soga, Masahiro NishijimaRyo Taguchi, Michinori Kohara

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish
Article numbere1002860
JournalPLoS Pathogens
Volume8
Issue number8
DOIs
Publication statusPublished - 2012 Aug 1

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Hirata, Y., Ikeda, K., Sudoh, M., Tokunaga, Y., Suzuki, A., Weng, L., Ohta, M., Tobita, Y., Okano, K., Ozeki, K., Kawasaki, K., Tsukuda, T., Katsume, A., Aoki, Y., Umehara, T., Sekiguchi, S., Toyoda, T., Shimotohno, K., Soga, T., ... Kohara, M. (2012). Self-Enhancement of Hepatitis C Virus Replication by Promotion of Specific Sphingolipid Biosynthesis. PLoS Pathogens, 8(8), [e1002860]. https://doi.org/10.1371/journal.ppat.1002860