The relevance of lipid droplet biogenesis to the hepatitis C virus replication organelle

• Applicant: Gabrielle Vieyres, Ph.D.
• Subject Area: Virology ; Cell Biology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 417852234

• Final Report Year: 2025

Final Report Abstract

Lipid droplets (LDs), the cell’s fat storage organelles, have become increasingly recognized for their roles in the life cycles of various pathogens. They are crucial for hepatitis C virus (HCV) particle formation and also help create the replication organelles of picornaviruses. In this study, we discovered that excessive lipid droplet formation—triggered by overexpressing the triglyceride-synthesizing enzyme DGAT2—actually hinders HCV replication. Specifically, high DGAT2 levels disrupt the formation and maintenance of the viral replication organelle. This heightened lipid droplet biogenesis led to significant changes in the cell’s lipid profile, including a marked accumulation of neutral lipids and alterations in membrane lipid composition. Our findings suggest that the flow of lipids during droplet formation influences the makeup of endoplasmic reticulum (ER) membranes, where lipid droplets originate. This, in turn, affects HCV’s ability to remodel these membranes into its replication organelle. Previous studies have shown that DGAT1-driven triglyceride synthesis supports HCV assembly. Our results suggest that not only the activity of DGAT1 and DGAT2, but also the interactions at membrane contact sites between the ER and lipid droplets, may locally regulate where HCV replication and assembly factories form. This highlights a complex interplay between lipid metabolism and viral replication, suggesting that the balance and localization of lipid droplet biogenesis are critical for the HCV replication cycle. These results may also be relevant for other positive-strand RNA viruses that remodel host membranes. The main findings were published in PLoS Pathogens 1.

Publications

• Lipid droplet biogenesis modulates hepatitis C virus genome replication. 21st French-speaking virology meeting, Lyon, France, 2019
  Gabrielle Vieyres
  
• The ATGL lipase cooperates with ABHD5 to mobilize lipids for hepatitis C virus assembly. PLOS Pathogens, 16(6), e1008554.
  Vieyres, Gabrielle; Reichert, Isabelle; Carpentier, Arnaud; Vondran, Florian W. R. & Pietschmann, Thomas
  
• Lipid Droplet Contact Sites in Health and Disease. Trends in Cell Biology, 31(5), 345-358.
  Herker, Eva; Vieyres, Gabrielle; Beller, Mathias; Krahmer, Natalie & Bohnert, Maria
  
• PicPreview and PicSummary: Two Timesaving Plugins for the Fluorescence Microscopist. Cells, 10(4), 846.
  Vieyres, Gabrielle
  
• Lipid droplet biogenesis modulates the formation of the hepatitis C virus replication organelle. Oral presentation at the Viruses 2022 conference (“At the leading Edge of Virology Research”, online)
  Isabelle Reichert
  
• Lipid droplet biogenesis modulates the formation of the hepatitis C virus replication organelle. Poster and selected pitch talk at the 31st annual meeting of the Society of Virology, Münich / online, 2022
  Isabelle Reichert
  
• The Railmap of Type I Interferon Induction: Subcellular Network Plan and How Viruses Can Change Tracks. Cells, 11(19), 3149.
  Weber, Laura & Vieyres, Gabrielle
  
• Lipid droplet biogenesis modulates the formation of the hepatitis C virus replication organelle. Oral presentation at the Gordon Research Conference “Molecular and Cellular Biology of Lipids”, Waterville Valley, USA, 2023
  Isabelle Reichert
  
• Lipid droplet biogenesis modulates the formation of the hepatitis C virus replication organelle. Poster at the 32nd annual meeting of the Society of Virology, Ulm, 2023
  Isabelle Reichert
  
• The role of human lipoproteins for hepatitis C virus persistence. Current Opinion in Virology, 60, 101327.
  Vieyres, Gabrielle & Pietschmann, Thomas
  
• The triglyceride-synthesizing enzyme diacylglycerol acyltransferase 2 modulates the formation of the hepatitis C virus replication organelle. PLOS Pathogens, 20(9), e1012509.
  Reichert, Isabelle; Lee, Ji-Young; Weber, Laura; Fuh, Marceline M.; Schlaeger, Lina; Rößler, Stefanie; Kinast, Volker; Schlienkamp, Sarah; Conradi, Janina; Vondran, Florian W. R.; Pfaender, Stephanie; Scaturro, Pietro; Steinmann, Eike; Bartenschlager, Ralf; Pietschmann, Thomas; Heeren, Joerg; Lauber, Chris & Vieyres, Gabrielle
  
• “The relevance of lipid droplet biogenesis to the hepatitis C virus replication organelle”. PhD thesis, University of Hamburg, Faculty of Chemistry, 2024
  Isabelle Reichert