Complex lipid metabolic remodeling is required for efficient hepatitis C virus replication

Autor: Rudolph Reimer, Sarah Hofmann, Christina Scherer, Eva Herker, Anja Schöbel, Dominik Schwudke, Pavel Truschow, Verena Scholz, Valerie Mordhorst, Matthias Krajewski
Rok vydání: 2017
Předmět:
0301 basic medicine
Fatty Acid Desaturases
Fatty Acid Elongases
Membrane lipids
Hepacivirus
Endoplasmic Reticulum
Virus Replication
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Acetyltransferases
Lipid droplet
Cell Line
Tumor
Microsomes
Lipidomics
Humans
RNA
Small Interfering
Molecular Biology
Triglycerides
chemistry.chemical_classification
Cholesterol
Virus Assembly
Virion
Lipid metabolism
Cell Biology
Lipid Droplets
Lipid Metabolism
030104 developmental biology
Viral replication
Biochemistry
chemistry
Gene Expression Regulation
Virion assembly
030220 oncology & carcinogenesis
Host-Pathogen Interactions
Fatty Acids
Unsaturated
Hepatocytes
Metabolome
Phosphatidylcholines
RNA
Viral
lipids (amino acids
peptides
and proteins)
Polyunsaturated fatty acid
Oleic Acid
Zdroj: Biochimica et biophysica acta. Molecular and cell biology of lipids. 1863(9)
ISSN: 1388-1981
Popis: The hepatitis C virus (HCV) life cycle is tightly linked to the host cell lipid metabolism with the endoplasmic reticulum-derived membranous web harboring viral RNA replication complexes and lipid droplets as virion assembly sites. To investigate HCV-induced changes in the lipid composition, we performed quantitative shotgun lipidomic studies of whole cell extracts and subcellular compartments. Our results indicate that HCV infection reduces the ratio of neutral to membrane lipids. While the amount of neutral lipids and lipid droplet morphology were unchanged, membrane lipids, especially cholesterol and phospholipids, accumulated in the microsomal fraction in HCV-infected cells. In addition, HCV-infected cells had a higher relative abundance of phosphatidylcholines and triglycerides with longer fatty acyl chains and a strikingly increased utilization of C18 fatty acids, most prominently oleic acid (FA [18:1]). Accordingly, depletion of fatty acid elongases and desaturases impaired HCV replication. Moreover, the analysis of free fatty acids revealed increased levels of polyunsaturated fatty acids (PUFAs) caused by HCV infection. Interestingly, inhibition of the PUFA synthesis pathway via knockdown of the rate-limiting Δ6-desaturase enzyme or by treatment with a high dose of a small-molecule inhibitor impaired viral progeny production, indicating that elevated PUFAs are needed for virion morphogenesis. In contrast, pretreatment with low inhibitor concentrations promoted HCV translation and/or early RNA replication. Taken together our results demonstrate the complex remodeling of the host cell lipid metabolism induced by HCV to enhance both virus replication and progeny production.
Databáze: OpenAIRE
Externí odkaz: