期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 23, 期 2, 页码 -出版社
MDPI
DOI: 10.3390/ijms23020919
关键词
hepatitis C virus; NS5A; glycolysis; glucokinase; lipogenesis; human lipoprotein; central carbon metabolism; hepatocyte
资金
- Fondation pour la Recherche Medicale (FRM)
- Agence Nationale de Recherches sur le Sida et les hepatites virales (ANRS|Maladies infectieuses emergentes)
The HCV protein NS5A activates the glucokinase isoenzyme to redirect central carbon metabolism towards lipogenesis, contributing to the replication needs of the virus.
Hepatitis C virus (HCV) relies on cellular lipid metabolism for its replication, and actively modulates lipogenesis and lipid trafficking in infected hepatocytes. This translates into an intracellular accumulation of triglycerides leading to liver steatosis, cirrhosis and hepatocellular carcinoma, which are hallmarks of HCV pathogenesis. While the interaction of HCV with hepatocyte metabolic pathways is patent, how viral proteins are able to redirect central carbon metabolism towards lipogenesis is unclear. Here, we report that the HCV protein NS5A activates the glucokinase (GCK) isoenzyme of hexokinases through its D2 domain (NS5A-D2). GCK is the first rate-limiting enzyme of glycolysis in normal hepatocytes whose expression is replaced by the hexokinase 2 (HK2) isoenzyme in hepatocellular carcinoma cell lines. We took advantage of a unique cellular model specifically engineered to re-express GCK instead of HK2 in the Huh7 cell line to evaluate the consequences of NS5A-D2 expression on central carbon and lipid metabolism. NS5A-D2 increased glucose consumption but decreased glycogen storage. This was accompanied by an altered mitochondrial respiration, an accumulation of intracellular triglycerides and an increased production of very-low density lipoproteins. Altogether, our results show that NS5A-D2 can reprogram central carbon metabolism towards a more energetic and glycolytic phenotype compatible with HCV needs for replication.
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