PMID:24390321

Citation	Ramière, C, Rodriguez, J, Enache, LS, Lotteau, V, André, P and Diaz, O (2014) Activity of hexokinase is increased by its interaction with hepatitis C virus protein NS5A. J. Virol. 88:3246-54
Abstract	The study of cellular central carbon metabolism modulations induced by viruses is an emerging field. Human cytomegalovirus (HCMV), herpes simplex virus (HSV), Kaposi's sarcoma-associated herpesvirus (KSHV), and hepatitis C virus (HCV) have been shown recently to reprogram cell metabolism to support their replication. During HCV infection the global glucidolipidic metabolism of hepatocytes is highly impacted. It was suggested that HCV might modify glucose uptake and glycolysis to increase fatty acids synthesis, but underlying mechanisms have not been completely elucidated. We thus investigated how HCV may modulate glycolysis. We observed that in infected Huh7.5 cells and in subgenomic replicon-positive Huh9.13 cells, glucose consumption as well as lactate secretion was increased. Using protein complementation assays and coimmunoprecipitation, we identified a direct interaction between the HCV NS5A protein and cellular hexokinase 2 (HK2), the first rate-limiting enzyme of glycolysis. NS5A expression was sufficient to enhance glucose consumption and lactate secretion in Huh7.5 cells. Moreover, determination of HK activity in cell homogenates revealed that addition of exogenous NS5A protein, either the full-length protein or its D2 or D3, but not D1, domain, was sufficient to increase enzyme activity. Finally, determination of recombinant HK2 catalytic parameters (V(max) and K(m)) in the presence of NS5A identified this viral protein as an activator of the enzyme. In summary, this study describes a direct interaction between HCV NS5A protein and cellular HK2 which is accompanied by an increase in HK2 activity that might contribute to an increased glycolysis rate during HCV infection.
Links	PubMed PMC3957934 Online version:10.1128/JVI.02862-13
Keywords	Cell Line; Glucose/metabolism; Glycolysis; Hepacivirus/enzymology; Hepacivirus/genetics; Hepatitis C/enzymology; Hepatitis C/genetics; Hepatitis C/metabolism; Hepatitis C/virology; Hexokinase/genetics; Hexokinase/metabolism; Humans; Protein Binding; Up-Regulation; Viral Nonstructural Proteins/genetics; Viral Nonstructural Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HCVH:POLG		GO:1903301: positive regulation of hexokinase activity	ECO:0000314:		P		Figure 7 shows statistically significant increases in hexokinase activity due to NS5A. Hepatitis C NS5A was used on Human Hexokinase	complete CACAO 13339
HCVH:POLG		GO:0019054: modulation by virus of host process	ECO:0000314:		P		Figures 6 and 7 show that Hepatitis C Virus NS5A affect Human Glycolysis.	complete CACAO 13342

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