Host phosphatidic acid phosphatase lipin1 is rate limiting for functional hepatitis C virus replicase complex formation

Autor: Xavier Forns, Victoria Castro, María Josefa Rodríguez, Lidia Mingorance, Sofía Pérez-del-Pulgar, Gema Calvo, José L. Carrascosa, Pablo Gastaminza, Ginés Ávila-Pérez
Jazyk: angličtina
Rok vydání: 2018
Předmět:
RNA viruses
0301 basic medicine
Physiology
Hepacivirus
Virus Replication
medicine.disease_cause
Biochemistry
Phosphatidate
RNA interference
Medicine and Health Sciences
Homeostasis
RNA
Small Interfering

Biology (General)
Pathology and laboratory medicine
Hepatitis C virus
Medical microbiology
Lipids
Hepatitis C
Enzymes
Cell biology
Infectious Diseases
Viruses
Host-Pathogen Interactions
RNA
Viral

Pathogens
Cellular Structures and Organelles
Oxidoreductases
Luciferase
Research Article
Infectious Disease Control
QH301-705.5
Immunology
Phosphatidate Phosphatase
RNA-dependent RNA polymerase
Biology
Biosynthesis
Microbiology
Cell Line
03 medical and health sciences
Virology
Genetics
medicine
Phospholipid homeostasis
Humans
Vesicles
RNA
Messenger

Molecular Biology
Diacylglycerol kinase
Biology and life sciences
Flaviviruses
030102 biochemistry & molecular biology
Organisms
Viral pathogens
Proteins
Lipid metabolism
Cell Biology
RC581-607
Lipid Metabolism
RNA-Dependent RNA Polymerase
Hepatitis viruses
Viral Replication
Microbial pathogens
Metabolism
030104 developmental biology
Viral replication
Enzymology
Parasitology
Immunologic diseases. Allergy
Physiological Processes
Zdroj: PLoS Pathogens, Vol 14, Iss 9, p e1007284 (2018)
PLOS Pathogens
PLoS Pathogens
ISSN: 1553-7374
1553-7366
Popis: Hepatitis C virus (HCV) infection constitutes a significant health burden worldwide, because it is a major etiologic agent of chronic liver disease, cirrhosis and hepatocellular carcinoma. HCV replication cycle is closely tied to lipid metabolism and infection by this virus causes profound changes in host lipid homeostasis. We focused our attention on a phosphatidate phosphate (PAP) enzyme family (the lipin family), which mediate the conversion of phosphatidate to diacylglycerol in the cytoplasm, playing a key role in triglyceride biosynthesis and in phospholipid homeostasis. Lipins may also translocate to the nucleus to act as transcriptional regulators of genes involved in lipid metabolism. The best-characterized member of this family is lipin1, which cooperates with lipin2 to maintain glycerophospholipid homeostasis in the liver. Lipin1-deficient cell lines were generated by RNAi to study the role of this protein in different steps of HCV replication cycle. Using surrogate models that recapitulate different aspects of HCV infection, we concluded that lipin1 is rate limiting for the generation of functional replicase complexes, in a step downstream primary translation that leads to early HCV RNA replication. Infection studies in lipin1-deficient cells overexpressing wild type or phosphatase-defective lipin1 proteins suggest that lipin1 phosphatase activity is required to support HCV infection. Finally, ultrastructural and biochemical analyses in replication-independent models suggest that lipin1 may facilitate the generation of the membranous compartment that contains functional HCV replicase complexes.
Author summary Hepatitis C virus (HCV) infection is an important biomedical problem worldwide because it causes severe liver disease and cancer. Although immunological events are major players in HCV pathogenesis, interference with host cell metabolism contribute to HCV-associated pathologies. HCV utilizes resources of the cellular lipid metabolism to strongly modify subcellular compartments, using them as platforms for replication and infectious particle assembly. In particular, HCV induces the formation of a “membranous web” that hosts the viral machinery dedicated to the production of new copies of the viral genome. This lipid-rich structure provides an optimized platform for viral genome replication and hides new viral genomes from host´s antiviral surveillance. In this study, we have identified a cellular protein, lipin1, involved in the production of a subset of cellular lipids, as a rate-limiting factor for HCV infection. Our results indicate that the enzymatic activity of lipin1 is required to build the membranous compartment dedicated to viral genome replication. Lipin1 is probably contributing to the formation of the viral replication machinery by locally providing certain lipids required for an optimal membranous environment. Based on these results, interfering with lipin1 capacity to modify lipids may therefore constitute a potential strategy to limit HCV infection.
Databáze: OpenAIRE
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