Reprogramming of Central Carbon Metabolism in Myeloid Cells upon Innate Immune Receptor Stimulation

Perrin-Cocon, Laure; Diaz, Olivier; Aublin-Gex, Anne; Vidalain, Pierre‐Olivier; Lotteau, Vincent

doi:10.3390/immuno1010001

Cited by 3 publications

(2 citation statements)

References 79 publications

(133 reference statements)

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“…HKs are the first ratelimiting enzymes of glucose catabolism and, therefore, control the entry of glucose-derived carbons into the CCM. Intermediate metabolites in the CCM such as glycerol-3P and citrate for lipogenesis and pentose-P for NADPH production largely depend on glycolysis activity [45]. We show here that HCV-NS5A, through its domain 2, decreases GCK allosteric regulation and increases its activity (Figure 5 and Figure S3).…”

Section: Discussionmentioning

confidence: 69%

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

Perrin-Cocon

Kundlacz

Jacquemin

et al. 2022

IJMS

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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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Section: Discussionmentioning

confidence: 69%

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

Perrin-Cocon

Kundlacz

Jacquemin

et al. 2022

IJMS

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“…Cellular metabolism can greatly vary during activation of the innate immune response and it has been widely observed that reprogramming of cell metabolism can reallocate cellular resources for the achievement of specific immune functions ( 3 ). Indeed, cells are using carbohydrates, especially glucose that is degraded by glycolysis into pyruvate, to produce ATP and metabolic precursors for other pathways ( Figure 1 ).…”

Section: Cross-talk Between Cellular Metabolism and Key Signaling Pat...mentioning

confidence: 99%

What role for cellular metabolism in the control of hepatitis viruses?

Diaz

Vidalain²,

Ramière³

et al. 2022

Front. Immunol.

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Hepatitis B, C and D viruses (HBV, HCV, HDV, respectively) specifically infect human hepatocytes and often establish chronic viral infections of the liver, thus escaping antiviral immunity for years. Like other viruses, hepatitis viruses rely on the cellular machinery to meet their energy and metabolite requirements for replication. Although this was initially considered passive parasitism, studies have shown that hepatitis viruses actively rewire cellular metabolism through molecular interactions with specific enzymes such as glucokinase, the first rate-limiting enzyme of glycolysis. As part of research efforts in the field of immunometabolism, it has also been shown that metabolic changes induced by viruses could have a direct impact on the innate antiviral response. Conversely, detection of viral components by innate immunity receptors not only triggers the activation of the antiviral defense but also induces in-depth metabolic reprogramming that is essential to support immunological functions. Altogether, these complex triangular interactions between viral components, innate immunity and hepatocyte metabolism may explain why chronic hepatitis infections progressively lead to liver inflammation and progression to cirrhosis, fibrosis and hepatocellular carcinoma (HCC). In this manuscript, we first present a global overview of known connections between the innate antiviral response and cellular metabolism. We then report known molecular mechanisms by which hepatitis viruses interfere with cellular metabolism in hepatocytes and discuss potential consequences on the innate immune response. Finally, we present evidence that drugs targeting hepatocyte metabolism could be used as an innovative strategy not only to deprive viruses of key metabolites, but also to restore the innate antiviral response that is necessary to clear infection.

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Immunometabolic interplay in Edwardsiella tarda-infected crucian carp (Carassius auratus) and in vitro identification of the antimicrobial activity of apolipoprotein D (ApoD) by utilization of multiomics analyses

Wang,

Xiong,

et al. 2024

International Journal of Biological Macromolecules

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Reprogramming of Central Carbon Metabolism in Myeloid Cells upon Innate Immune Receptor Stimulation

Cited by 3 publications

References 79 publications

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

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

What role for cellular metabolism in the control of hepatitis viruses?

Immunometabolic interplay in Edwardsiella tarda-infected crucian carp (Carassius auratus) and in vitro identification of the antimicrobial activity of apolipoprotein D (ApoD) by utilization of multiomics analyses

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