Domain 2 of Hepatitis C Virus Protein NS5A Activates Glucokinase and Induces Lipogenesis in Hepatocytes

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.

Download Full-text

Hepatitis C Virus Protein Interaction Network Analysis Based on Hepatocellular Carcinoma

PLoS ONE ◽

10.1371/journal.pone.0153882 ◽

2016 ◽

Vol 11 (4) ◽

pp. e0153882 ◽

Cited By ~ 7

Author(s):

Yuewen Han ◽

Jun Niu ◽

Dong Wang ◽

Yuanyuan Li

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Network Analysis ◽

Protein Interaction ◽

Protein Interaction Network ◽

Interaction Network ◽

Virus Protein

Download Full-text

Human Cytomegalovirus Remodeling of Lipid Metabolism Requires pUL37x1

10.1101/526228 ◽

2019 ◽

Cited By ~ 1

Author(s):

John G Purdy ◽

Yuecheng Xi ◽

Samuel Harwood ◽

Lisa Wise

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Human Cytomegalovirus ◽

Carbon Metabolism ◽

Central Carbon Metabolism ◽

Host Factors ◽

Fatty Acid Elongation ◽

Metabolic Remodeling ◽

Central Carbon ◽

Hcmv Replication

Human cytomegalovirus (HCMV) replication requires remodeling of the host metabolic network, including increasing central carbon metabolism, fatty acid elongation and lipid synthesis. The virus-host interactions regulating HCMV metabolic hijacking are essential to infection. While multiple host factors including kinases and transcription factors have been defined, little is known about the viral factors required. Some host factors involved are dependent on Ca2+ signaling or host stress response. The viral pUL37x1 protein mobilizes Ca2+ and targets the mitochondria. The Ca2+ changes induced by pUL37x1 can activate stress responses. In this study, we tested the hypothesis that the viral pUL37x1 protein is required for HCMV metabolic remodeling. Using a combination of metabolomics, lipidomics, and metabolic tracers, we demonstrate that pUL37x1 protein is necessary for HCMV induced fatty acid elongation and lipid metabolism but not required for most viral hijacking of central carbon metabolism. Additionally, we show that pUL37x1 is required for HCMV to fully induce two host proteins that were previously demonstrated to be important for virus induced lipid metabolism: fatty acid elongase 7 and the ER-stress related kinase PERK. We also demonstrate, for the first time, that HCMV replication results in the increase in phospholipids with very-long chain fatty acyl tails. We conclude that pUL37x1 is required for HCMV metabolic remodeling but is not necessary to for the virus to hijack metabolism on a network-wide scale.

Download Full-text