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Temporal Proteome and Lipidome Profiles Reveal Hepatitis C Virus-Associated Reprogramming of Hepatocellular Metabolism and Bioenergetics


Proteomic and lipidomic profiling was performed over a time course of acute hepatitis C virus (HCV) infection in cultured Huh-7.5 cells to gain new insights into the intracellular processes influenced by this virus. Our proteomic data suggest that HCV induces early perturbations in glycolysis, the pentose phosphate pathway, and the citric acid cycle, which favor host biosynthetic activities supporting viral replication and propagation. This is followed by a compensatory shift in metabolism aimed at maintaining energy homeostasis and cell viability during elevated viral replication and increasing cellular stress. Complementary lipidomic analyses identified numerous temporal perturbations in select lipid species (e.g. phospholipids and sphingomyelins) predicted to play important roles in viral replication and downstream assembly and secretion events. The elevation of lipotoxic ceramide species suggests a potential link between HCV-associated biochemical alterations and the direct cytopathic effect observed in this in vitro system. Using innovative computational modeling approaches, we further identified mitochondrial fatty acid oxidation enzymes, which are comparably regulated during in vitro infection and in patients with histological evidence of fibrosis, as possible targets through which HCV regulates temporal alterations in cellular metabolic homeostasis.


Vyšlo v časopise: Temporal Proteome and Lipidome Profiles Reveal Hepatitis C Virus-Associated Reprogramming of Hepatocellular Metabolism and Bioenergetics. PLoS Pathog 6(1): e32767. doi:10.1371/journal.ppat.1000719
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000719

Souhrn

Proteomic and lipidomic profiling was performed over a time course of acute hepatitis C virus (HCV) infection in cultured Huh-7.5 cells to gain new insights into the intracellular processes influenced by this virus. Our proteomic data suggest that HCV induces early perturbations in glycolysis, the pentose phosphate pathway, and the citric acid cycle, which favor host biosynthetic activities supporting viral replication and propagation. This is followed by a compensatory shift in metabolism aimed at maintaining energy homeostasis and cell viability during elevated viral replication and increasing cellular stress. Complementary lipidomic analyses identified numerous temporal perturbations in select lipid species (e.g. phospholipids and sphingomyelins) predicted to play important roles in viral replication and downstream assembly and secretion events. The elevation of lipotoxic ceramide species suggests a potential link between HCV-associated biochemical alterations and the direct cytopathic effect observed in this in vitro system. Using innovative computational modeling approaches, we further identified mitochondrial fatty acid oxidation enzymes, which are comparably regulated during in vitro infection and in patients with histological evidence of fibrosis, as possible targets through which HCV regulates temporal alterations in cellular metabolic homeostasis.


Zdroje

1. AlterMJ

MargolisHS

KrawczynskiK

JudsonFN

MaresA

1992 The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med 327 1899 1905

2. IkedaM

KatoN

2007 Modulation of host metabolism as a target of new antivirals. Adv Drug Deliv Rev 59 1277 1289

3. HeY

DuanW

TanSL

2007 Emerging host cell targets for hepatitis C therapy. Drug Discov Today 12 209 217

4. YeJ

2007 Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus. PLoS Pathog 3 e108 doi:10.1371/journal.ppat.0030108

5. NegroF

SanyalAJ

2009 Hepatitis C virus, steatosis and lipid abnormalities: clinical and pathogenic data. Liver Int S2 26 37

6. ShiST

LeeKJ

AizakiH

HwangSB

LaiMM

2003 Hepatitis C virus RNA replication occurs on a detergent-resistant membrane that cofractionates with caveolin 2. J Virol 77 4160 4168

7. KapadiaSB

ChisariFV

2005 Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci U S A 102 2561 2566

8. WangC

GaleMJr

KellerBC

HuangH

BrownMS

2005 Identification of FBL2 as a geranylgeranylated cellular protein required for hepatitis C virus RNA replication. Mol Cell 18 425 434

9. SakamotoH

OkamotoK

AokiM

KatoH

KatsumeA

2005 Host sphingolipid biosynthesis as a target for hepatitis C virus therapy. Nat Chem Biol 1 333 337

10. UmeharaT

SudohM

YasuiF

MatsudaC

HayashiY

2006 Serine palmitoyltransferase inhibitor suppresses HCV replication in a mouse model. Biochem Biophys Res Commun 346 67 73

11. MiyanariY

AtsuzawaK

UsudaN

WatashiK

HishikiT

2007 The lipid droplet is an important organelle for hepatitis C virus production. Nat Cell Biol 9 1089 1097

12. HuangH

SunF

OwenDM

LiW

ChenY

2007 Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low density lipoproteins. Proc Natl Acad Sci U S A 104 5848 5853

13. GastaminzaP

ChengG

WielandS

ZhongJ

LiaoW

2008 Cellular determinants of hepatitis C virus assembly, maturation, degradation, and secretion. J Virol 82 2120 2129

14. YaoH

YeJ

2008 Long chain acyl-CoA synthetase 3-mediated phosphatidylcholine synthesis is required for assembly of very low density lipoproteins in human hepatoma Huh7 cells. J Biol Chem 283 849 854

15. NahmiasY

GoldwasserJ

CasaliM

van PollD

WakitaT

2008 Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology 47 1437 1445

16. AizakiH

MorikawaK

FukasawaM

HaraH

InoueY

2008 Critical role of virion-associated cholesterol and sphingolipid in hepatitis C virus infection. J Virol 82 5715 5724

17. WaltersKA

SyderAJ

LedererSL

DiamondDL

PaeperB

2009 Genomic analysis reveals a potential role for cell cycle perturbation in HCV-mediated apoptosis of cultured hepatocytes. PLoS Pathog 5 e1000269 doi:10.1371/journal.ppat.1000269

18. LindenbachBD

EvansMJ

SyderAJ

WölkB

TellinghuisenTL

2005 Complete replication of hepatitis C virus in cell culture. Science 309 623 626

19. QianWJ

MonroeME

LiuT

JacobsJM

AndersonGA

2005 Quantitative Proteome Analysis of Human Plasma following in Vivo Lipopolysaccharide Administration Using 16O/18O Labeling and the Accurate Mass and Time Tag Approach. Mol Cell Proteomics 4 700 709

20. DiamondDL

JacobsJM

PaeperB

ProllSC

GritsenkoMA

2007 Proteomic Profiling of Human Liver Biopsies: Hepatitis C Virus-Induced Fibrosis and Mitochondrial Dysfunction. Hepatology 46 649 657

21. JacobsJM

DiamondDL

ChanEY

GritsenkoMA

QianW

2005 Proteome analysis of liver cells expressing a full-length hepatitis C virus (HCV) replicon and biopsy specimens of posttransplantation liver from HCV-infected patients. J Virol 79 7558 7569

22. ShenY

ZhaoR

BelovME

ConradsTP

AndersonGA

2001 Packed capillary reversed-phase liquid chromatography with high-performance electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry for proteomics. Anal Chem 73 1766 1775

23. LivesayEA

TangK

TaylorBK

BuschbachMA

HopkinsDF

2008 Fully automated four-column capillary LC-MS system for maximizing throughput in proteomic analyses. Anal Chem 80 294 302

24. DingJ

SorensenCM

ZhangQ

JiangH

JaitlyN

2007 Capillary LC coupled with high-mass measurement accuracy mass spectrometry for metabolic profiling. Anal Chem 79 6081 6093

25. KiebelGR

AuberryKJ

JaitlyN

ClarkDA

MonroeME

2006 PRISM: A data management system for high-throughput proteomics. Proteomics 60 1783 1790

26. JaitlyN

MayampurathA

LittlefieldK

AdkinsJN

AndersonGA

2009 Decon2LS: An open-source software package for automated processing and visualization of high resolution Mass Spectrometry Data. BMC Bioinformatics 10 87

27. MonroeME

TolićN

JaitlyN

ShawJL

AdkinsJN

2007 VIPER: an advanced software package to support high-throughput LC-MS peptide identification. Bioinformatics 23 2021 2023

28. JaitlyN

MonroeME

PetyukVA

ClaussTR

AdkinsJN

2006 Robust algorithm for alignment of liquid chromatography-mass spectrometry analyses in an accurate mass and time tag data analysis pipeline. Anal Chem 78 7397 7409

29. YaoX

FreasA

RamirezJ

DemirevPA

FenselauC

2001 Protelytic 180 Labeling for Comparative Proteomics: Model Studies with Two Serotypes of Adenovirus. Anal Chem 73 2836 2842

30. NesvizhskiiAI

KellerA

KolkerE

AebersoldR

2003 A Statistical Model for Identifying Proteins by Tandem Mass Spectrometry. Anal Chem 75 4646 4658

31. TryggJ

HolmesE

LundstedtT

2007 Chemometrics in metabonomics. J Proteome Res 6 469 79

32. YuH

KimPM

SprecherE

TrifonovV

GersteinM

2007 The importance of bottlenecks in protein networks: correlation with gene essentiality and expression dynamics. PLoS Comput Biol 3 e59 doi:10.1371/journal.pcbi.0030059

33. DyerMD

MuraliTM

SobralBW

2008 The landscape of human proteins interacting with viruses and other pathogens. PLoS Pathog 4 e32 doi:10.1371/journal.ppat.0040032

34. McDermottJE

TaylorRC

YoonH

HeffronF

2009 Bottlenecks and hubs in inferred networks are important for virulence in Salmonella typhimurium. J Comput Biol 16 169 180

35. DiamondDL

ProllSC

JacobsJM

ChanEY

CampDG2nd

2006 HepatoProteomics: applying proteomic technologies to the study of liver function and disease. Hepatology 44 299 308

36. DeBerardinisRJ

LumJJ

HatzivassiliouG

ThompsonCB

2008 The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7 11 20

37. DeBerardinisRJ

MancusoA

DaikhinE

NissimI

YudkoffM

2007 Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 104 19345 19350

38. StuyverLJ

McBrayerTR

TharnishPM

HassanAE

ChuCK

2003 Dynamics of subgenomic hepatitis C virus replicon RNA levels in Huh-7 cells after exposure to nucleoside antimetabolites. J Virol 77 10689 10694

39. OwenOE

KalhanSC

HansonRW

2002 The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem 277 30409 30412

40. YooH

AntoniewiczMR

StephanopoulosG

KelleherJK

2008 Quantifying reductive carboxylation flux of glutamine to lipid in a brown adipocyte cell line. J Biol Chem 283 20621 20627

41. TardifKD

MoriK

SiddiquiA

2002 Hepatitis C virus subgenomic replicons induce endoplasmic reticulum stress activating an intracellular signaling pathway. J Virol 76 7453 7459

42. PavioN

RomanoPR

GraczykTM

FeinstoneSM

TaylorDR

2003 Protein synthesis and endoplasmic reticulum stress can be modulated by the hepatitis C virus envelope protein E2 through the eukaryotic initiation factor 2alpha kinase PERK. J Virol 77 3578 3585

43. MiccheliAT

MiccheliA

Di ClementeR

ValerioM

ColucciaP

2006 NMR-based metabolic profiling of human hepatoma cells in relation to cell growth by culture media analysis. Biochim Biophys Acta 1760 1723 1731

44. LangPA

SchenckM

NicolayJP

BeckerJU

KempeDS

2007 Liver cell death and anemia in Wilson disease involve acid sphingomyelinase and ceramide. Nat Med 13 164 170

45. VoissetC

LavieM

HelleF

Op De BeeckA

BilheuA

2008 Ceramide enrichment of the plasma membrane induces CD81 internalization and inhibits hepatitis C virus entry. Cell Microbiol 10 606 617

46. de ChasseyB

NavratilV

TafforeauL

HietMS

Aublin-GexA

2008 Hepatitis C virus infection protein network. Mol Syst Biol 4 230

47. MungerJ

BajadSU

CollerHA

ShenkT

RabinowitzJD

2006 Dynamics of the cellular metabolome during human cytomegalovirus infection. PLoS Pathog 2 e132 doi:10.1371/journal.ppat.0020132

48. MungerJ

BennettBD

ParikhA

FengXJ

McArdleJ

2008 Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy. Nat Biotechnol 26 1179 1186

49. ChanEY

QianWJ

DiamondDL

LiuT

GritsenkoMA

2007 Quantitative analysis of human immunodeficiency virus type 1-infected CD4+ cell proteome: dysregulated cell cycle progression and nuclear transport coincide with robust virus production. J Virol 81 7571 7583

50. ChanEY

SuttonJN

JacobsJM

BondarenkoA

SmithRD

2009 Dynamic Host Energetics and Cytoskeletal Proteomes in HIV-1-Infected Human Primary CD4 Cells: Analysis by Multiplexed Label-free Mass Spectrometry. J Virol 83 9283 9295

51. RingroseJH

JeeningaRE

BerkhoutB

SpeijerD

2008 Proteomic studies reveal coordinated changes in T-cell expression patterns upon infection with human immunodeficiency virus type 1. J Virol 82 4320 4330

52. van 't WoutAB

SwainJV

SchindlerM

RaoU

PathmajeyanMS

2005 Nef induces multiple genes involved in cholesterol synthesis and uptake in human immunodeficiency virus type 1-infected T cells. J Virol 79 10053 10058

53. PiccoliC

ScrimaR

QuaratoG

D'AprileA

RipoliM

2007 Hepatitis C virus protein expression causes calcium-mediated mitochondrial bioenergetic dysfunction and nitro-oxidative stress. Hepatology 46 58 65

54. ChenEI

HewelJ

KruegerJS

TirabyC

WeberMR

2007 Adaptation of energy metabolism in breast cancer brain metastases. Cancer Res 67 1472 1486

55. Abu-ElheigaL

MatzukMM

Abo-HashemaKA

WakilSJ

2001 Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291 2613 2616

56. YuXX

LewinDA

ForrestW

AdamsSH

2002 Cold elicits the simultaneous induction of fatty acid synthesis and beta-oxidation in murine brown adipose tissue: prediction from differential gene expression and confirmation in vivo. FASEB J 16 155 168

57. DullooAG

GublerM

MontaniJP

SeydouxJ

SolinasG

2004 Substrate cycling between de novo lipogenesis and lipid oxidation: a thermogenic mechanism against skeletal muscle lipotoxicity and glucolipotoxicity. Int J Obes Relat Metab Disord Suppl 4 S29 837

58. KasaiD

AdachiT

DengL

Nagano-FujiiM

SadaK

2009 HCV replication suppresses cellular glucose uptake through down-regulation of cell surface expression of glucose transporters. J Hepatol 50 883 894

59. GaleMJr

TanSL

KatzeMG

2000 Translational control of viral gene expression in eukaryotes. Microbiol Mol Biol Rev 64 239 280

60. KrützfeldtJ

RajewskyN

BraichR

RajeevKG

TuschlT

2005 Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438 685 689

61. EsauC

DavisS

MurraySF

YuXX

PandeySK

2006 miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 3 87 98

62. JoplingCL

YiM

LancasterAM

LemonSM

SarnowP

2005 Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 309 1577 1581

63. SchwanhäusserB

GossenM

DittmarG

SelbachM

2009 Global analysis of cellular protein translation by pulsed SILAC. Proteomics 9 205 209

64. BrüggerB

GlassB

HaberkantP

LeibrechtI

WielandFT

2006 The HIV lipidome: A raft with an unusual composition. Proc Natl Acad Sci U S A 103 2641 2646

65. CallahanMK

PopernackPM

TsutsuiS

TruongL

SchlegelRA

2003 Phosphatidylserine on HIV Envelope Is a Cofactor for Infection of Monocytic Cells. J Immunol 170 4840 4845

66. KapadiaSB

ChisariFV

2005 Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. Proc Natl Acad Sci U S A 102 2561 2566

67. TakahashiM

WatariE

ShinyaE

ShimizuT

TakahashiH

2007 Suppression of virus replication via down-modulation of mitochondrial short chain enoyl-CoA hydratase in human glioblastoma cells. Antiviral Res 75 152 158

68. PengX

ChanEY

LiY

DiamondDL

KorthMJ

2009 Virus-host interactions: from systems biology to translational research. Curr Opin Microbiol 12 432 438

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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