Enhanced Hepatitis C Virus Genome Replication and Lipid Accumulation Mediated by Inhibition of AMP-activated Protein Kinase

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Jun 11

PMID 20534540

Citations 87

Authors

Jamel Mankouri

Philip R Tedbury

Sarah Gretton

Mair E Hughes

Stephen D C Griffin

Mark L Dallas

Kevin A Green

D Grahame Hardie

Chris Peers

Mark Harris

Affiliations

Soon will be listed here.

Abstract

Hepatitis C virus (HCV) infection is associated with dysregulation of both lipid and glucose metabolism. As well as contributing to viral replication, these perturbations influence the pathogenesis associated with the virus, including steatosis, insulin resistance, and type 2 diabetes. AMP-activated protein kinase (AMPK) plays a key role in regulation of both lipid and glucose metabolism. We show here that, in cells either infected with HCV or harboring an HCV subgenomic replicon, phosphorylation of AMPK at threonine 172 and concomitant AMPK activity are dramatically reduced. We demonstrate that this effect is mediated by activation of the serine/threonine kinase, protein kinase B, which inhibits AMPK by phosphorylating serine 485. The physiological significance of this inhibition is demonstrated by the observation that pharmacological restoration of AMPK activity not only abrogates the lipid accumulation observed in virus-infected and subgenomic replicon-harboring cells but also efficiently inhibits viral replication. These data demonstrate that inhibition of AMPK is required for HCV replication and that the restoration of AMPK activity may present a target for much needed anti-HCV therapies.

Citing Articles

LKB1 suppresses KSHV reactivation and promotes primary effusion lymphoma progression.

Li G, Li Y, Tang X, Wang L, Yue S, He S J Virol. 2024; 98(9):e0060424.

PMID: 39194241 PMC: 11406988. DOI: 10.1128/jvi.00604-24.

Fine-tuning AMPK in physiology and disease using point-mutant mouse models.

Ashraf N, Van Nostrand J Dis Model Mech. 2024; 17(8).

PMID: 39136185 PMC: 11340815. DOI: 10.1242/dmm.050798.

Hepatitis C Virus Dysregulates Polyamine and Proline Metabolism and Perturbs the Urea Cycle.

Zakirova N, Khomich O, Smirnova O, Molle J, Duponchel S, Yanvarev D Cells. 2024; 13(12.

PMID: 38920664 PMC: 11201506. DOI: 10.3390/cells13121036.

AMPK protects endothelial cells against HSV-1 replication via inhibition of mTORC1 and ACC1.

Doshi H, Spengler K, Godbole A, Gee Y, Baell J, Oakhill J Microbiol Spectr. 2023; :e0041723.

PMID: 37702499 PMC: 10580915. DOI: 10.1128/spectrum.00417-23.

Hepatitis C virus non-structural proteins modulate cellular kinases for increased cytoplasmic abundance of host factor HuR and facilitate viral replication.

Raheja H, George B, Tripathi S, Saha S, Maiti T, Das S PLoS Pathog. 2023; 19(8):e1011552.

PMID: 37540723 PMC: 10431626. DOI: 10.1371/journal.ppat.1011552.

References

McLauchlan J . Lipid droplets and hepatitis C virus infection. Biochim Biophys Acta. 2009; 1791(6):552-9. DOI: 10.1016/j.bbalip.2008.12.012. View

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J . Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8):1167-74. PMC: 209533. DOI: 10.1172/JCI13505. View

Gastaminza P, Cheng G, Wieland S, Zhong J, Liao W, Chisari F . Cellular determinants of hepatitis C virus assembly, maturation, degradation, and secretion. J Virol. 2007; 82(5):2120-9. PMC: 2258938. DOI: 10.1128/JVI.02053-07. View

Horman S, Vertommen D, Heath R, Neumann D, Mouton V, Woods A . Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase alpha-subunits in heart via hierarchical phosphorylation of Ser485/491. J Biol Chem. 2005; 281(9):5335-40. DOI: 10.1074/jbc.M506850200. View

Hardie D, Hawley S . AMP-activated protein kinase: the energy charge hypothesis revisited. Bioessays. 2001; 23(12):1112-9. DOI: 10.1002/bies.10009. View

Hawley S, Boudeau J, Reid J, Mustard K, Udd L, Makela T . Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003; 2(4):28. PMC: 333410. DOI: 10.1186/1475-4924-2-28. View

Wolf D, Witte V, Laffert B, Blume K, Stromer E, Trapp S . HIV-1 Nef associated PAK and PI3-kinases stimulate Akt-independent Bad-phosphorylation to induce anti-apoptotic signals. Nat Med. 2001; 7(11):1217-24. DOI: 10.1038/nm1101-1217. View

Grahame Hardie D . AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007; 8(10):774-85. DOI: 10.1038/nrm2249. View

Zhang H, Wu M . SIRT1 regulates Tat-induced HIV-1 transactivation through activating AMP-activated protein kinase. Virus Res. 2009; 146(1-2):51-7. DOI: 10.1016/j.virusres.2009.08.005. View

10.

Street A, MacDonald A, Crowder K, Harris M . The Hepatitis C virus NS5A protein activates a phosphoinositide 3-kinase-dependent survival signaling cascade. J Biol Chem. 2004; 279(13):12232-41. DOI: 10.1074/jbc.M312245200. View

11.

Hughes M, Gretton S, Shelton H, Brown D, McCormick C, Angus A . A conserved proline between domains II and III of hepatitis C virus NS5A influences both RNA replication and virus assembly. J Virol. 2009; 83(20):10788-96. PMC: 2753128. DOI: 10.1128/JVI.02406-08. View

12.

Corton J, Gillespie J, Hawley S, Hardie D . 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells?. Eur J Biochem. 1995; 229(2):558-65. DOI: 10.1111/j.1432-1033.1995.tb20498.x. View

13.

Kapadia S, Chisari F . Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci U S A. 2005; 102(7):2561-6. PMC: 549027. DOI: 10.1073/pnas.0409834102. View

14.

Lochhead P, Salt I, Walker K, Hardie D, Sutherland C . 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes. 2000; 49(6):896-903. DOI: 10.2337/diabetes.49.6.896. View

15.

Oem J, Jackel-Cram C, Li Y, Zhou Y, Zhong J, Shimano H . Activation of sterol regulatory element-binding protein 1c and fatty acid synthase transcription by hepatitis C virus non-structural protein 2. J Gen Virol. 2008; 89(Pt 5):1225-1230. DOI: 10.1099/vir.0.83491-0. View

16.

Tscherne D, Jones C, Evans M, Lindenbach B, McKeating J, Rice C . Time- and temperature-dependent activation of hepatitis C virus for low-pH-triggered entry. J Virol. 2006; 80(4):1734-41. PMC: 1367161. DOI: 10.1128/JVI.80.4.1734-1741.2006. View

17.

Krieger N, Lohmann V, Bartenschlager R . Enhancement of hepatitis C virus RNA replication by cell culture-adaptive mutations. J Virol. 2001; 75(10):4614-24. PMC: 114214. DOI: 10.1128/JVI.75.10.4614-4624.2001. View

18.

Machado M, Cortez-Pinto H . Insulin resistance and steatosis in chronic hepatitis C. Ann Hepatol. 2009; 8 Suppl 1:S67-75. View

19.

Zheng Y, Plemenitas A, Fielding C, Peterlin B . Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions. Proc Natl Acad Sci U S A. 2003; 100(14):8460-5. PMC: 166251. DOI: 10.1073/pnas.1437453100. View

20.

Kapadia S, Barth H, Baumert T, McKeating J, Chisari F . Initiation of hepatitis C virus infection is dependent on cholesterol and cooperativity between CD81 and scavenger receptor B type I. J Virol. 2006; 81(1):374-83. PMC: 1797271. DOI: 10.1128/JVI.01134-06. View