AMP-Activated Protein Kinase Restricts Zika Virus Replication in Endothelial Cells by Potentiating Innate Antiviral Responses and Inhibiting Glycolysis
- 20 February 2020
- journal article
- research article
- Published by The American Association of Immunologists in Journal Of Immunology
- Vol. 204 (7), 1810-1824
- https://doi.org/10.4049/jimmunol.1901310
Abstract
Viruses are known to perturb host cellular metabolism to enable their replication and spread. However, little is known about the interactions between Zika virus (ZIKV) infection and host metabolism. Using primary human retinal vascular endothelial cells and an established human endothelial cell line, we investigated the role of AMP-activated protein kinase (AMPK), a master regulator of energy metabolism, in response to ZIKV challenge. ZIKV infection caused a time-dependent reduction in the active phosphorylated state of AMPK and of its downstream target acetyl-CoA carboxylase. Pharmacological activation of AMPK using 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), metformin, and a specific AMPK alpha activator (GSK621) attenuated ZIKV replication. This activity was reversed by an AMPK inhibitor (compound C). Lentivirus-mediated knockdown of AMPK and the use of AMPK alpha(-/-) mouse embryonic fibroblasts provided further evidence that AMPK has an antiviral effect on ZIKV replication. Consistent with its antiviral effect, AMPK activation potentiated the expression of genes with antiviral properties (e.g., IFNs, OAS2, ISG15, and MX/) and inhibited inflammatory mediators (e.g., TNF-alpha and CCL5). Bioenergetic analysis showed that ZIKV infection evokes a glycolytic response, as evidenced by elevated extracellular acidification rate and increased expression of key glycolytic genes (GLUT1, HK2, TPI, and MCT4); activation of AMPK by AICAR treatment reduced this response. Consistent with this, 2-deoxyglucose, an inhibitor of glycolysis, augmented AMPK activity and attenuated ZIKV replication. Thus, our study demonstrates that the anti-ZIKV effect of AMPK signaling in endothelial cells is mediated by reduction of viral-induced glycolysis and enhanced innate antiviral responses.This publication has 73 references indexed in Scilit:
- AMP-Activated Kinase Restricts Rift Valley Fever Virus Infection by Inhibiting Fatty Acid SynthesisPLoS Pathogens, 2012
- Productive Dengue Virus Infection of Human Endothelial Cells Is Directed by Heparan Sulfate-Containing Proteoglycan ReceptorsJournal of Virology, 2011
- Endothelial Cells Are Central Orchestrators of Cytokine Amplification during Influenza Virus InfectionCell, 2011
- Viruses and the fuel sensor: the emerging link between AMPK and virus replicationReviews in Medical Virology, 2011
- AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1Nature, 2011
- Energy Homeostasis and Cancer Prevention: The AMP-Activated Protein KinaseCancer Prevention Research, 2009
- AMP-activated/SNF1 protein kinases: conserved guardians of cellular energyNature Reviews Molecular Cell Biology, 2007
- Localization of Dengue Virus in Naturally Infected Human Tissues, by Immunohistochemistry and In Situ HybridizationThe Journal of Infectious Diseases, 2004
- 5-Aminoimidazole-4-Carboxamide-1-β-4-Ribofuranoside Inhibits Proinflammatory Response in Glial Cells: A Possible Role of AMP-Activated Protein KinaseJournal of Neuroscience, 2004
- Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinaseBiochemical Society Transactions, 2002