title: PTEN protein phosphatase activity regulates hepatitis C virus secretion through modulation of cholesterol metabolism.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) infection is dependent on lipid metabolism. Hepatocyte steatosis occurs frequently in HCV infection, but the relationship between steatosis and HCV life cycle is unclear. We showed that HCV induces steatosis via the downregulation of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). We here investigated how PTEN may affect HCV production.
  
  
  METHODS
  The effect of overexpression or silencing of PTEN on HCV secretion was assessed in genomic-length Jc1 infected HuH7 cells. The role of PTEN protein and lipid phosphatase activities on lipid metabolism and infectious viral particle secretion was investigated using dominant-negative PTEN mutants. The importance of cholesterol metabolism for PTEN-dependent lipid droplet biogenesis and viral particle secretion was examined using statins.
  
  
  RESULTS
  PTEN silencing in Jc1 infected HuH7 cells stimulated HCV particle secretion, while PTEN overexpression decreased virus egress. Viral secretion was also increased by overexpression of protein phosphatase-deleted (PTENY138L), but not lipid phosphatase-deleted (PTENG129E), PTEN mutant, thus indicating that the protein phosphatase activity of PTEN controls viral secretion. Similarly, PTENY138L, but not PTENG129E mutant induced the formation of large lipid droplets. PTENY138L mutant did not affect biosynthesis of triglycerides, but promoted the biosynthesis of cholesterol esters. Consistently, statins prevented the increased cholesterol ester production, large lipid droplet formation, and viral secretion in cells expressing the PTENY138L mutant.
  
  
  CONCLUSIONS
  Downregulation of PTEN protein phosphatase activity by HCV affects cholesterol metabolism, thereby inducing the appearance of large lipid droplets and increasing virion egress.
authors.affiliation: Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Marion
authors.initials: M
authors.lastname: Peyrou
authors.forename: Sophie
authors.initials: S
authors.lastname: Clément
authors.forename: Christiane
authors.initials: C
authors.lastname: Maier
authors.forename: Lucie
authors.initials: L
authors.lastname: Bourgoin
authors.forename: Emilie
authors.initials: E
authors.lastname: Branche
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Conzelmann
authors.forename: Vincent
authors.initials: V
authors.lastname: Kaddai
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Foti
authors.forename: Francesco
authors.initials: F
authors.lastname: Negro
mesh_terms: D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D015536:Down-Regulation; D016174:Hepacivirus / Q000472:pathogenicity / Q000502:physiology*; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D057074:Virus Release / Q000235:genetics / Q000502:physiology
chemical_list: D002788:Cholesterol Esters; D034741:RNA, Small Interfering; D002784:Cholesterol; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: CE; HCC; HCV; LD; Lipid droplets; Liver; NAFLD; ORO; Oil-Red-O; PI; PTEN; Statin; Steatosis; TG; Viral particle assembly; cholesterol ester; hepatitis C virus; hepatocellular carcinoma; lipid droplet; non-alcoholic fatty liver disease; phophatase and tensin homolog deleted on chromosome 10; phosphoinositide; triglyceride