Self-enhancement of hepatitis C virus replication by promotion of specific sphingolipid biosynthesis.
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.
Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan.
Yuichi
Y
Hirata
Kazutaka
K
Ikeda
Masayuki
M
Sudoh
Yuko
Y
Tokunaga
Akemi
A
Suzuki
Leiyun
L
Weng
Masatoshi
M
Ohta
Yoshimi
Y
Tobita
Ken
K
Okano
Kazuhisa
K
Ozeki
Kenichi
K
Kawasaki
Takuo
T
Tsukuda
Asao
A
Katsume
Yuko
Y
Aoki
Takuya
T
Umehara
Satoshi
S
Sekiguchi
Tetsuya
T
Toyoda
Kunitada
K
Shimotohno
Tomoyoshi
T
Soga
Masahiro
M
Nishijima
Ryo
R
Taguchi
Michinori
M
Kohara
D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013107:Sphingolipids / Q000096:biosynthesis* / Q000235:genetics; D017855:Transferases (Other Substituted Phosphate Groups) / Q000096:biosynthesis; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D013107:Sphingolipids; D051102:Serine C-Palmitoyltransferase; C455440:SGMS1 protein, human; D017855:Transferases (Other Substituted Phosphate Groups)