Glycometabolism regulates hepatitis C virus release
| Autor: | Haishuang Chang, Yongning He, Tao Yu, Qiankun Yang, Fangling Tian, Lin Han, Yifan Xing, Yaming Jiu, Jin Zhong, Bowen Yu, Zhenzheng Hu |
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| Rok vydání: | 2021 |
| Předmět: |
RNA viruses
Metabolic Processes 0301 basic medicine Physiology Hepacivirus Biochemistry Virions 0302 clinical medicine Animal Cells Immune Physiology Post-Translational Modification Phosphorylation Biology (General) Pathology and laboratory medicine Virus Release Innate Immune System Organic Compounds Hepatitis C virus Chemistry Monosaccharides virus diseases Medical microbiology Hepatitis C Cell biology Liver Virion assembly 030220 oncology & carcinogenesis Physical Sciences Viruses Cytokines Pathogens Cellular Types Anatomy Glycolysis Intracellular Research Article QH301-705.5 Immunology Carbohydrates Oxidative phosphorylation Viral Structure Microbiology Virus 03 medical and health sciences Immune system Cell Line Tumor Virology Genetics Humans Secretion Molecular Biology Medicine and health sciences Biology and life sciences Flaviviruses Organic Chemistry Chemical Compounds Organisms Viral pathogens Galactose Proteins Cell Biology Molecular Development RC581-607 Hepatitis viruses digestive system diseases Microbial pathogens Glucose Metabolism 030104 developmental biology Anaerobic glycolysis Immune System Hepatocytes Parasitology Immunologic diseases. Allergy Developmental Biology |
| Zdroj: | PLoS Pathogens, Vol 17, Iss 7, p e1009746 (2021) PLoS Pathogens |
| ISSN: | 1553-7374 |
| Popis: | HCV cell-culture system uses hepatoma-derived cell lines for efficient virus propagation. Tumor cells cultured in glucose undergo active aerobic glycolysis, but switch to oxidative phosphorylation for energy production when cultured in galactose. Here, we investigated whether modulation of glycolysis in hepatocytes affects HCV infection. We showed HCV release, but not entry, genome replication or virion assembly, is significantly blocked when cells are cultured in galactose, leading to accumulation of intracellular infectious virions within multivesicular body (MVB). Blockade of the MVB-lysosome fusion or treatment with pro-inflammatory cytokines promotes HCV release in galactose. Furthermore, we found this glycometabolic regulation of HCV release is mediated by MAPK-p38 phosphorylation. Finally, we showed HCV cell-to-cell transmission is not affected by glycometabolism, suggesting that HCV cell-to-supernatant release and cell-to-cell transmission are two mechanistically distinct pathways. In summary, we demonstrated glycometabolism regulates the efficiency and route of HCV release. We proposed HCV may exploit the metabolic state in hepatocytes to favor its spread through the cell-to-cell transmission in vivo to evade immune response. Author summary Hepatitis C virus (HCV) is a positive-stranded RNA virus that causes acute and chronic hepatitis and hepatocellular carcinoma. HCV infectious cycle comprises viral entry, uncoating, translation and replication of viral RNA, assembly into new virions and release. Establishment of HCV cell culture system (HCVcc) has yielded many insights into complete HCV infectious cycle in Huh7 cell and Huh7-derived human hepatoma cell lines. However, because hepatoma-derived cell lines and hepatocytes vary in metabolism, HCV infectious cycle in tumor cell lines and the patient’s liver may also be different. Therefore, we explored the alterations of HCV infectious cycle by forcing the tumor cell lines to switch their glycometabolic pathways. We found that HCV release can be blocked by culturing cells in galactose-containing medium, leading to accumulation of intracellular infectious virions within MVB. Moreover, we provided new evidence to suggest that HCV cell-to-cell transmission may be mechanistically distinct from cell-to-supernatant release. Finally, we proposed a new concept that HCV release from hepatocytes into circulation may be naturally inefficient due to the metabolic state in liver that may favor more HCV cell-to-cell transmission. This strategy would allow HCV to effectively evade neutralizing antibodies to establish persistent infection. |
| Databáze: | OpenAIRE |
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