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 language | English |
|---|---|
| Article number | e1002860 |
| Journal | PLoS Pathogens |
| Volume | 8 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2012 Aug |
Fingerprint
ASJC Scopus subject areas
- Microbiology
- Parasitology
- Virology
- Immunology
- Genetics
- Molecular Biology
Cite this
Self-Enhancement of Hepatitis C Virus Replication by Promotion of Specific Sphingolipid Biosynthesis. / Hirata, Yuichi; Ikeda, Kazutaka; Sudoh, Masayuki; Tokunaga, Yuko; Suzuki, Akemi; Weng, Leiyun; Ohta, Masatoshi; Tobita, Yoshimi; Okano, Ken; Ozeki, Kazuhisa; Kawasaki, Kenichi; Tsukuda, Takuo; Katsume, Asao; Aoki, Yuko; Umehara, Takuya; Sekiguchi, Satoshi; Toyoda, Tetsuya; Shimotohno, Kunitada; Soga, Tomoyoshi; Nishijima, Masahiro; Taguchi, Ryo; Kohara, Michinori.
In: PLoS Pathogens, Vol. 8, No. 8, e1002860, 08.2012.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Self-Enhancement of Hepatitis C Virus Replication by Promotion of Specific Sphingolipid Biosynthesis
AU - Hirata, Yuichi
AU - Ikeda, Kazutaka
AU - Sudoh, Masayuki
AU - Tokunaga, Yuko
AU - Suzuki, Akemi
AU - Weng, Leiyun
AU - Ohta, Masatoshi
AU - Tobita, Yoshimi
AU - Okano, Ken
AU - Ozeki, Kazuhisa
AU - Kawasaki, Kenichi
AU - Tsukuda, Takuo
AU - Katsume, Asao
AU - Aoki, Yuko
AU - Umehara, Takuya
AU - Sekiguchi, Satoshi
AU - Toyoda, Tetsuya
AU - Shimotohno, Kunitada
AU - Soga, Tomoyoshi
AU - Nishijima, Masahiro
AU - Taguchi, Ryo
AU - Kohara, Michinori
PY - 2012/8
Y1 - 2012/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84866174396&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84866174396&partnerID=8YFLogxK
U2 - 10.1371/journal.ppat.1002860
DO - 10.1371/journal.ppat.1002860
M3 - Article
VL - 8
JO - PLoS Pathogens
JF - PLoS Pathogens
SN - 1553-7366
IS - 8
M1 - e1002860
ER -