Skip to main content

Structural Proteins of HCV and Biological Functions

  • Chapter
  • First Online:
Hepatitis C Virus I

Abstract

Hepatitis C virus (HCV) is a major causative agent of liver disorders and a major risk factor for hepatocellular carcinoma. The induction of hepatocellular carcinoma by HCV is thought to involve not only chronic inflammation, but also the biological activity of HCV components. Structural proteins of HCV are composed of the core protein and two envelope proteins, E1 and E2. The HCV core protein has been reported to exhibit multiple biological functions involved in lipid synthesis, iron metabolism, insulin response, oxidative stress and cell growth, and to thereby contribute to the development of carcinogenesis and metabolic disorders. Moreover, several reports suggest that envelope proteins also play an important role in viral entry as well as HCV-related pathogenic events. However, the mechanism by which the structural proteins induce hepatitis C-related disorders has not been fully understood. This review focuses on the current status of biological responses mediated by HCV structural proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abid K, Pazienza V, de Gottardi A, Rubbia-Brandt L, Conne B, Pugnale P, Rossi C, Mangia A, Negro F (2005) An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulation. J Hepatol 42(5):744–751

    Article  CAS  PubMed  Google Scholar 

  • Adinolfi LE, Restivo L, Zampino R, Lonardo A, Loria P (2011) Metabolic alterations and chronic hepatitis C: treatment strategies. Expert Opin Pharmacother 12(14):2215–2234

    Article  CAS  PubMed  Google Scholar 

  • Aguirre V, Uchida T, Yenush L, Davis R, White MF (2000) The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem 275(12):9047–9054

    Article  CAS  PubMed  Google Scholar 

  • Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF (2002) Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem 277(2):1531–1537

    Article  CAS  PubMed  Google Scholar 

  • Akuta N, Suzuki F, Sezaki H, Suzuki Y, Hosaka T, Someya T, Kobayashi M, Saitoh S, Watahiki S, Sato J, Matsuda M, Kobayashi M, Arase Y, Ikeda K, Kumada H (2005) Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy. Intervirology 48(6):372–380

    Article  CAS  PubMed  Google Scholar 

  • Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Chayama K, Nakamura Y, Kumada H (2010) Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology 52(2):421–429

    Article  CAS  PubMed  Google Scholar 

  • Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15(23):6541–6551

    CAS  PubMed  PubMed Central  Google Scholar 

  • Allen SJ, Mott KR, Matsuura Y, Moriishi K, Kousoulas KG, Ghiasi H (2014) Binding of HSV-1 glycoprotein K (gK) to signal peptide peptidase (SPP) is required for virus infectivity. PLoS One 9(1):e85360

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Andre P, Komurian-Pradel F, Deforges S, Perret M, Berland JL, Sodoyer M, Pol S, Brechot C, Paranhos-Baccala G, Lotteau V (2002) Characterization of low- and very-low-density hepatitis C virus RNA-containing particles. J Virol 76(14):6919–6928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andriopoulos B Jr, Corradini E, Xia Y, Faasse SA, Chen S, Grgurevic L, Knutson MD, Pietrangelo A, Vukicevic S, Lin HY, Babitt JL (2009) BMP6 is a key endogenous regulator of hepcidin expression and iron metabolism. Nat Genet 41(4):482–487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Balasubramanian A, Ganju RK, Groopman JE (2006) Signal transducer and activator of transcription factor 1 mediates apoptosis induced by hepatitis C virus and HIV envelope proteins in hepatocytes. J Infect Dis 194(5):670–681

    Article  CAS  PubMed  Google Scholar 

  • Banerjee S, Saito K, Ait-Goughoulte M, Meyer K, Ray RB, Ray R (2008) Hepatitis C virus core protein upregulates serine phosphorylation of insulin receptor substrate-1 and impairs the downstream akt/protein kinase B signaling pathway for insulin resistance. J Virol 82(6):2606–2612

    Article  CAS  PubMed  Google Scholar 

  • Barba G, Harper F, Harada T, Kohara M, Goulinet S, Matsuura Y, Eder G, Schaff Z, Chapman MJ, Miyamura T, Brechot C (1997) Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. Proc Natl Acad Sci U S A 94(4):1200–1205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bartolomei G, Cevik RE, Marcello A (2011) Modulation of hepatitis C virus replication by iron and hepcidin in Huh7 hepatocytes. J Gen Virol 92(Pt 9):2072–2081

    Article  CAS  PubMed  Google Scholar 

  • Bartosch B, Vitelli A, Granier C, Goujon C, Dubuisson J, Pascale S, Scarselli E, Cortese R, Nicosia A, Cosset FL (2003) Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor. J Biol Chem 278(43):41624–41630

    Article  CAS  PubMed  Google Scholar 

  • Bassett SE, Di Bisceglie AM, Bacon BR, Sharp RM, Govindarajan S, Hubbard GB, Brasky KM, Lanford RE (1999) Effects of iron loading on pathogenicity in hepatitis C virus-infected chimpanzees. Hepatology 29(6):1884–1892

    Article  CAS  PubMed  Google Scholar 

  • Benali-Furet NL, Chami M, Houel L, De Giorgi F, Vernejoul F, Lagorce D, Buscail L, Bartenschlager R, Ichas F, Rizzuto R, Paterlini-Brechot P (2005) Hepatitis C virus core triggers apoptosis in liver cells by inducing ER stress and ER calcium depletion. Oncogene 24(31):4921–4933

    Article  CAS  PubMed  Google Scholar 

  • Benedicto I, Molina-Jimenez F, Barreiro O, Maldonado-Rodriguez A, Prieto J, Moreno-Otero R, Aldabe R, Lopez-Cabrera M, Majano PL (2008) Hepatitis C virus envelope components alter localization of hepatocyte tight junction-associated proteins and promote occludin retention in the endoplasmic reticulum. Hepatology 48(4):1044–1053

    Article  CAS  PubMed  Google Scholar 

  • Bergqvist A, Sundstrom S, Dimberg LY, Gylfe E, Masucci MG (2003) The hepatitis C virus core protein modulates T cell responses by inducing spontaneous and altering T-cell receptor-triggered Ca2+ oscillations. J Biol Chem 278(21):18877–18883

    Article  CAS  PubMed  Google Scholar 

  • Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2(6):326–332

    Article  CAS  PubMed  Google Scholar 

  • Bigger CB, Guerra B, Brasky KM, Hubbard G, Beard MR, Luxon BA, Lemon SM, Lanford RE (2004) Intrahepatic gene expression during chronic hepatitis C virus infection in chimpanzees. J Virol 78(24):13779–13792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonkovsky HL (2002) Iron as a comorbid factor in chronic viral hepatitis. Am J Gastroenterol 97(1):1–4

    Article  CAS  PubMed  Google Scholar 

  • Bose SK, Kim H, Meyer K, Wolins N, Davidson NO, Ray R (2014) Forkhead box transcription factor regulation and lipid accumulation by hepatitis C virus. J Virol 88(8):4195–4203

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Boucher E, Bourienne A, Adams P, Turlin B, Brissot P, Deugnier Y (1997) Liver iron concentration and distribution in chronic hepatitis C before and after interferon treatment. Gut 41(1):115–120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boyer A, Dumans A, Beaumont E, Etienne L, Roingeard P, Meunier JC (2014) The association of hepatitis C virus glycoproteins with apolipoproteins E and B early in assembly is conserved in lipoviral particles. J Biol Chem 289(27):18904–18913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bradley D, McCaustland K, Krawczynski K, Spelbring J, Humphrey C, Cook EH (1991) Hepatitis C virus: buoyant density of the factor VIII-derived isolate in sucrose. J Med Virol 34(3):206–208

    Article  CAS  PubMed  Google Scholar 

  • Burbelo PD, Dubovi EJ, Simmonds P, Medina JL, Henriquez JA, Mishra N, Wagner J, Tokarz R, Cullen JM, Iadarola MJ, Rice CM, Lipkin WI, Kapoor A (2012) Serology-enabled discovery of genetically diverse hepaciviruses in a new host. J Virol 86(11):6171–6178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Burgering BM, Coffer PJ (1995) Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376(6541):599–602

    Article  CAS  PubMed  Google Scholar 

  • Cavaghan MK, Ehrmann DA, Polonsky KS (2000) Interactions between insulin resistance and insulin secretion in the development of glucose intolerance. J Clin Invest 106(3):329–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan SW, Egan PA (2005) Hepatitis C virus envelope proteins regulate CHOP via induction of the unfolded protein response. FASEB J Off Publ Fed Am Soc Exp Biol 19(11):1510–1512

    CAS  Google Scholar 

  • Chen PC, Chuang PK, Chen CH, Chan YT, Chen JR, Lin SW, Ma C, Hsu TL, Wong CH (2014) Role of N-linked glycans in the interactions of recombinant HCV envelope glycoproteins with cellular receptors. ACS Chem Biol 9(7):1437–1443

    Article  CAS  PubMed  Google Scholar 

  • Chiou HL, Hsieh YS, Hsieh MR, Chen TY (2006) HCV E2 may induce apoptosis of Huh-7 cells via a mitochondrial-related caspase pathway. Biochem Biophys Res Commun 345(1):453–458

    Article  CAS  PubMed  Google Scholar 

  • Cho H, Lee HC, Jang SK, Kim YK (2008) Iron increases translation initiation directed by internal ribosome entry site of hepatitis C virus. Virus Genes 37(2):154–160

    Article  CAS  PubMed  Google Scholar 

  • Dao Thi VL, Granier C, Zeisel MB, Guerin M, Mancip J, Granio O, Penin F, Lavillette D, Bartenschlager R, Baumert TF, Cosset FL, Dreux M (2012) Characterization of hepatitis C virus particle subpopulations reveals multiple usage of the scavenger receptor BI for entry steps. J Biol Chem 287(37):31242–31257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deleersnyder V, Pillez A, Wychowski C, Blight K, Xu J, Hahn YS, Rice CM, Dubuisson J (1997) Formation of native hepatitis C virus glycoprotein complexes. J Virol 71(1):697–704

    CAS  PubMed  PubMed Central  Google Scholar 

  • Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20(5):649–688

    CAS  PubMed  Google Scholar 

  • Dharancy S, Malapel M, Perlemuter G, Roskams T, Cheng Y, Dubuquoy L, Podevin P, Conti F, Canva V, Philippe D, Gambiez L, Mathurin P, Paris JC, Schoonjans K, Calmus Y, Pol S, Auwerx J, Desreumaux P (2005) Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection. Gastroenterology 128(2):334–342

    Article  CAS  PubMed  Google Scholar 

  • Di Bisceglie AM, Axiotis CA, Hoofnagle JH, Bacon BR (1992) Measurements of iron status in patients with chronic hepatitis. Gastroenterology 102(6):2108–2113

    Article  PubMed  Google Scholar 

  • Draznin B (2006) Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85alpha: the two sides of a coin. Diabetes 55(8):2392–2397

    Article  CAS  PubMed  Google Scholar 

  • Drexler JF, Corman VM, Muller MA, Lukashev AN, Gmyl A, Coutard B, Adam A, Ritz D, Leijten LM, van Riel D, Kallies R, Klose SM, Gloza-Rausch F, Binger T, Annan A, Adu-Sarkodie Y, Oppong S, Bourgarel M, Rupp D, Hoffmann B, Schlegel M, Kummerer BM, Kruger DH, Schmidt-Chanasit J, Setien AA, Cottontail VM, Hemachudha T, Wacharapluesadee S, Osterrieder K, Bartenschlager R, Matthee S, Beer M, Kuiken T, Reusken C, Leroy EM, Ulrich RG, Drosten C (2013) Evidence for novel hepaciviruses in rodents. PLoS Pathog 9(6):e1003438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Evans MJ, von Hahn T, Tscherne DM, Syder AJ, Panis M, Wolk B, Hatziioannou T, McKeating JA, Bieniasz PD, Rice CM (2007) Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446(7137):801–805

    Article  CAS  PubMed  Google Scholar 

  • Foka P, Dimitriadis A, Kyratzopoulou E, Giannimaras DA, Sarno S, Simos G, Georgopoulou U, Mamalaki A (2014) A complex signaling network involving protein kinase CK2 is required for hepatitis C virus core protein-mediated modulation of the iron-regulatory hepcidin gene expression. Cell Mol Life Sci CMLS 71(21):4243–4258

    Article  CAS  PubMed  Google Scholar 

  • Fujita N, Sugimoto R, Urawa N, Araki J, Mifuji R, Yamamoto M, Horiike S, Tanaka H, Iwasa M, Kobayashi Y, Adachi Y, Kaito M (2007) Hepatic iron accumulation is associated with disease progression and resistance to interferon/ribavirin combination therapy in chronic hepatitis C. J Gastroenterol Hepatol 22(11):1886–1893

    Article  CAS  PubMed  Google Scholar 

  • Funaoka Y, Sakamoto N, Suda G, Itsui Y, Nakagawa M, Kakinuma S, Watanabe T, Mishima K, Ueyama M, Onozuka I, Nitta S, Kitazume A, Kiyohashi K, Murakawa M, Azuma S, Tsuchiya K, Watanabe M (2011) Analysis of interferon signaling by infectious hepatitis C virus clones with substitutions of core amino acids 70 and 91. J Virol 85(12):5986–5994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ganz T, Nemeth E (2012) Hepcidin and iron homeostasis. Biochim Biophys Acta 1823(9):1434–1443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao Z, Zuberi A, Quon MJ, Dong Z, Ye J (2003) Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J Biol Chem 278(27):24944–24950

    Article  CAS  PubMed  Google Scholar 

  • Gardner JP, Durso RJ, Arrigale RR, Donovan GP, Maddon PJ, Dragic T, Olson WC (2003) L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C virus. Proc Natl Acad Sci U S A 100(8):4498–4503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gardner BM, Pincus D, Gotthardt K, Gallagher CM, Walter P (2013) Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb Perspect Biol 5(3):a013169

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gavrilova O, Haluzik M, Matsusue K, Cutson JJ, Johnson L, Dietz KR, Nicol CJ, Vinson C, Gonzalez FJ, Reitman ML (2003) Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem 278(36):34268–34276

    Article  CAS  PubMed  Google Scholar 

  • Goffard A, Dubuisson J (2003) Glycosylation of hepatitis C virus envelope proteins. Biochimie 85(3–4):295–301

    Article  CAS  PubMed  Google Scholar 

  • Goffard A, Callens N, Bartosch B, Wychowski C, Cosset FL, Montpellier C, Dubuisson J (2005) Role of N-linked glycans in the functions of hepatitis C virus envelope glycoproteins. J Virol 79(13):8400–8409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graf E, Mahoney JR, Bryant RG, Eaton JW (1984) Iron-catalyzed hydroxyl radical formation. Stringent requirement for free iron coordination site. J Biol Chem 259(6):3620–3624

    CAS  PubMed  Google Scholar 

  • Grakoui A, McCourt DW, Wychowski C, Feinstone SM, Rice CM (1993a) Characterization of the hepatitis C virus-encoded serine proteinase: determination of proteinase-dependent polyprotein cleavage sites. J Virol 67(5):2832–2843

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grakoui A, McCourt DW, Wychowski C, Feinstone SM, Rice CM (1993b) A second hepatitis C virus-encoded proteinase. Proc Natl Acad Sci U S A 90(22):10583–10587

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grakoui A, Wychowski C, Lin C, Feinstone SM, Rice CM (1993c) Expression and identification of hepatitis C virus polyprotein cleavage products. J Virol 67(3):1385–1395

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gurav AN (2012) Periodontitis and insulin resistance: casual or causal relationship? Diabetes Metab J 36(6):404–411

    Article  PubMed  PubMed Central  Google Scholar 

  • Halilbasic E, Baghdasaryan A, Trauner M (2013) Nuclear receptors as drug targets in cholestatic liver diseases. Clin Liver Dis 17(2):161–189

    Article  PubMed  PubMed Central  Google Scholar 

  • Harada S, Watanabe Y, Takeuchi K, Suzuki T, Katayama T, Takebe Y, Saito I, Miyamura T (1991) Expression of processed core protein of hepatitis C virus in mammalian cells. J Virol 65(6):3015–3021

    CAS  PubMed  PubMed Central  Google Scholar 

  • Harbut MB, Patel BA, Yeung BK, McNamara CW, Bright AT, Ballard J, Supek F, Golde TE, Winzeler EA, Diagana TT, Greenbaum DC (2012) Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design. Proc Natl Acad Sci U S A 109(52):21486–21491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heimann M, Roman-Sosa G, Martoglio B, Thiel HJ, Rumenapf T (2006) Core protein of pestiviruses is processed at the C terminus by signal peptide peptidase. J Virol 80(4):1915–1921

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hijikata M, Kato N, Ootsuyama Y, Nakagawa M, Shimotohno K (1991) Gene mapping of the putative structural region of the hepatitis C virus genome by in vitro processing analysis. Proc Natl Acad Sci U S A 88(13):5547–5551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hijikata M, Shimizu YK, Kato H, Iwamoto A, Shih JW, Alter HJ, Purcell RH, Yoshikura H (1993) Equilibrium centrifugation studies of hepatitis C virus: evidence for circulating immune complexes. J Virol 67(4):1953–1958

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hope RG, McLauchlan J (2000) Sequence motifs required for lipid droplet association and protein stability are unique to the hepatitis C virus core protein. J Gen Virol 81(Pt 8):1913–1925

    Article  CAS  PubMed  Google Scholar 

  • Hope RG, Murphy DJ, McLauchlan J (2002) The domains required to direct core proteins of hepatitis C virus and GB virus-B to lipid droplets share common features with plant oleosin proteins. J Biol Chem 277(6):4261–4270

    Article  CAS  PubMed  Google Scholar 

  • Horton JD, Goldstein JL, Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109(9):1125–1131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsieh MJ, Lan KP, Liu HY, Zhang XZ, Lin YF, Chen TY, Chiou HL (2012) Hepatitis C virus E2 protein involve in insulin resistance through an impairment of Akt/PKB and GSK3beta signaling in hepatocytes. BMC Gastroenterol 12:74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Y, Feld JJ, Sapp RK, Nanda S, Lin JH, Blatt LM, Fried MW, Murthy K, Liang TJ (2007) Defective hepatic response to interferon and activation of suppressor of cytokine signaling 3 in chronic hepatitis C. Gastroenterology 132(2):733–744

    Article  CAS  PubMed  Google Scholar 

  • Hussy P, Langen H, Mous J, Jacobsen H (1996) Hepatitis C virus core protein: carboxy-terminal boundaries of two processed species suggest cleavage by a signal peptide peptidase. Virology 224(1):93–104

    Article  CAS  PubMed  Google Scholar 

  • Kahn BB (1998) Type 2 diabetes: when insulin secretion fails to compensate for insulin resistance. Cell 92(5):593–596

    Article  CAS  PubMed  Google Scholar 

  • Kapoor A, Simmonds P, Gerold G, Qaisar N, Jain K, Henriquez JA, Firth C, Hirschberg DL, Rice CM, Shields S, Lipkin WI (2011) Characterization of a canine homolog of hepatitis C virus. Proc Natl Acad Sci U S A 108(28):11608–11613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kapoor A, Simmonds P, Scheel TK, Hjelle B, Cullen JM, Burbelo PD, Chauhan LV, Duraisamy R, Sanchez Leon M, Jain K, Vandegrift KJ, Calisher CH, Rice CM, Lipkin WI (2013) Identification of rodent homologs of hepatitis C virus and pegiviruses. mBiol 4(2):e00216-00213

    Google Scholar 

  • Kawaguchi T, Yoshida T, Harada M, Hisamoto T, Nagao Y, Ide T, Taniguchi E, Kumemura H, Hanada S, Maeyama M, Baba S, Koga H, Kumashiro R, Ueno T, Ogata H, Yoshimura A, Sata M (2004) Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. Am J Pathol 165(5):1499–1508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khan AG, Whidby J, Miller MT, Scarborough H, Zatorski AV, Cygan A, Price AA, Yost SA, Bohannon CD, Jacob J, Grakoui A, Marcotrigiano J (2014) Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2. Nature 509(7500):381–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim S, Date T, Yokokawa H, Kono T, Aizaki H, Maurel P, Gondeau C, Wakita T (2014) Development of hepatitis C virus genotype 3a cell culture system. Hepatology in press. doi:10.1002/hep.27197

    Google Scholar 

  • Koike K, Tsutsumi T, Yotsuyanagi H, Moriya K (2010) Lipid metabolism and liver disease in hepatitis C viral infection. Oncology 78(Suppl 1):24–30

    Article  CAS  PubMed  Google Scholar 

  • Kojima E, Takeuchi A, Haneda M, Yagi A, Hasegawa T, Yamaki K, Takeda K, Akira S, Shimokata K, Isobe K (2003) The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress: elucidation by GADD34-deficient mice. FASEB J Off Publ Fed Am Soc Exp Biol 17(11):1573–1575

    CAS  Google Scholar 

  • Kong L, Giang E, Nieusma T, Kadam RU, Cogburn KE, Hua Y, Dai X, Stanfield RL, Burton DR, Ward AB, Wilson IA, Law M (2013) Hepatitis C virus E2 envelope glycoprotein core structure. Science 342(6162):1090–1094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Korenaga M, Wang T, Li Y, Showalter LA, Chan T, Sun J, Weinman SA (2005) Hepatitis C virus core protein inhibits mitochondrial electron transport and increases reactive oxygen species (ROS) production. J Biol Chem 280(45):37481–37488

    Article  CAS  PubMed  Google Scholar 

  • Krey T, d’Alayer J, Kikuti CM, Saulnier A, Damier-Piolle L, Petitpas I, Johansson DX, Tawar RG, Baron B, Robert B, England P, Persson MA, Martin A, Rey FA (2010) The disulfide bonds in glycoprotein E2 of hepatitis C virus reveal the tertiary organization of the molecule. PLoS Pathog 6(2):e1000762

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lavillette D, Pecheur EI, Donot P, Fresquet J, Molle J, Corbau R, Dreux M, Penin F, Cosset FL (2007) Characterization of fusion determinants points to the involvement of three discrete regions of both E1 and E2 glycoproteins in the membrane fusion process of hepatitis C virus. J Virol 81(16):8752–8765

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee YH, Giraud J, Davis RJ, White MF (2003) c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. J Biol Chem 278(5):2896–2902

    Article  CAS  PubMed  Google Scholar 

  • Lee SH, Kim YK, Kim CS, Seol SK, Kim J, Cho S, Song YL, Bartenschlager R, Jang SK (2005) E2 of hepatitis C virus inhibits apoptosis. J Immunol 175(12):8226–8235

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Boehning DF, Qian T, Popov VL, Weinman SA (2007) Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca2+ uniporter activity. FASEB J Off Publ Fed Am Soc Exp Biol 21(10):2474–2485

    CAS  Google Scholar 

  • Li X, Chen H, Oh SS, Chishti AH (2008) A Presenilin-like protease associated with Plasmodium falciparum micronemes is involved in erythrocyte invasion. Mol Biochem Parasitol 158(1):22–31

    Article  CAS  PubMed  Google Scholar 

  • Li G, Mongillo M, Chin KT, Harding H, Ron D, Marks AR, Tabas I (2009a) Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis. J Cell Biol 186(6):783–792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li HF, Huang CH, Ai LS, Chuang CK, Chen SS (2009b) Mutagenesis of the fusion peptide-like domain of hepatitis C virus E1 glycoprotein: involvement in cell fusion and virus entry. J Biomed Sci 16:89

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li X, Chen H, Bahamontes-Rosa N, Kun JF, Traore B, Crompton PD, Chishti AH (2009c) Plasmodium falciparum signal peptide peptidase is a promising drug target against blood stage malaria. Biochem Biophys Res Commun 380(3):454–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lima-Cabello E, Garcia-Mediavilla MV, Miquilena-Colina ME, Vargas-Castrillon J, Lozano-Rodriguez T, Fernandez-Bermejo M, Olcoz JL, Gonzalez-Gallego J, Garcia-Monzon C, Sanchez-Campos S (2011) Enhanced expression of pro-inflammatory mediators and liver X-receptor-regulated lipogenic genes in non-alcoholic fatty liver disease and hepatitis C. Clin Sci (Lond) 120(6):239–250

    Article  CAS  Google Scholar 

  • Liu X, Theil EC (2005) Ferritins: dynamic management of biological iron and oxygen chemistry. Acc Chem Res 38(3):167–175

    Article  CAS  PubMed  Google Scholar 

  • Loureiro J, Lilley BN, Spooner E, Noriega V, Tortorella D, Ploegh HL (2006) Signal peptide peptidase is required for dislocation from the endoplasmic reticulum. Nature 441(7095):894–897

    Article  CAS  PubMed  Google Scholar 

  • Lozach PY, Lortat-Jacob H, de Lacroix de Lavalette A, Staropoli I, Foung S, Amara A, Houles C, Fieschi F, Schwartz O, Virelizier JL, Arenzana-Seisdedos F, Altmeyer R (2003) DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2. J Biol Chem 278(22):20358–20366

    Article  CAS  PubMed  Google Scholar 

  • Lyons S, Kapoor A, Sharp C, Schneider BS, Wolfe ND, Culshaw G, Corcoran B, McGorum BC, Simmonds P (2012) Nonprimate hepaciviruses in domestic horses, United kingdom. Emerg Infect Dis 18(12):1976–1982

    Article  PubMed  PubMed Central  Google Scholar 

  • Machida K, Cheng KT, Lai CK, Jeng KS, Sung VM, Lai MM (2006) Hepatitis C virus triggers mitochondrial permeability transition with production of reactive oxygen species, leading to DNA damage and STAT3 activation. J Virol 80(14):7199–7207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Majeau N, Fromentin R, Savard C, Duval M, Tremblay MJ, Leclerc D (2009) Palmitoylation of hepatitis C virus core protein is important for virion production. J Biol Chem 284(49):33915–33925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7):1261–1274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuura Y, Harada S, Suzuki R, Watanabe Y, Inoue Y, Saito I, Miyamura T (1992) Expression of processed envelope protein of hepatitis C virus in mammalian and insect cells. J Virol 66(3):1425–1431

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mattijssen F, Kersten S (2012) Regulation of triglyceride metabolism by Angiopoietin-like proteins. Biochim Biophys Acta 1821(5):782–789

    Article  CAS  PubMed  Google Scholar 

  • McLauchlan J (2000) Properties of the hepatitis C virus core protein: a structural protein that modulates cellular processes. J Viral Hepat 7(1):2–14

    Article  CAS  PubMed  Google Scholar 

  • McLauchlan J, Lemberg MK, Hope G, Martoglio B (2002) Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. EMBO J 21(15):3980–3988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McPherson S, Jonsson JR, Barrie HD, O'Rourke P, Clouston AD, Powell EE (2008) Investigation of the role of SREBP-1c in the pathogenesis of HCV-related steatosis. J Hepatol 49(6):1046–1054

    Article  CAS  PubMed  Google Scholar 

  • Meynard D, Kautz L, Darnaud V, Canonne-Hergaux F, Coppin H, Roth MP (2009) Lack of the bone morphogenetic protein BMP6 induces massive iron overload. Nat Genet 41(4):478–481

    Article  CAS  PubMed  Google Scholar 

  • Mihm S, Fayyazi A, Hartmann H, Ramadori G (1997) Analysis of histopathological manifestations of chronic hepatitis C virus infection with respect to virus genotype. Hepatology 25(3):735–739

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto H, Moriishi K, Moriya K, Murata S, Tanaka K, Suzuki T, Miyamura T, Koike K, Matsuura Y (2007) Involvement of the PA28gamma-dependent pathway in insulin resistance induced by hepatitis C virus core protein. J Virol 81(4):1727–1735

    Article  CAS  PubMed  Google Scholar 

  • Miyanari Y, Atsuzawa K, Usuda N, Watashi K, Hishiki T, Zayas M, Bartenschlager R, Wakita T, Hijikata M, Shimotohno K (2007) The lipid droplet is an important organelle for hepatitis C virus production. Nat Cell Biol 9(9):1089–1097

    Article  CAS  PubMed  Google Scholar 

  • Miyoshi H, Fujie H, Shintani Y, Tsutsumi T, Shinzawa S, Makuuchi M, Kokudo N, Matsuura Y, Suzuki T, Miyamura T, Moriya K, Koike K (2005) Hepatitis C virus core protein exerts an inhibitory effect on suppressor of cytokine signaling (SOCS)-1 gene expression. J Hepatol 43(5):757–763

    Article  CAS  PubMed  Google Scholar 

  • Miyoshi H, Moriya K, Tsutsumi T, Shinzawa S, Fujie H, Shintani Y, Fujinaga H, Goto K, Todoroki T, Suzuki T, Miyamura T, Matsuura Y, Yotsuyanagi H, Koike K (2011) Pathogenesis of lipid metabolism disorder in hepatitis C: polyunsaturated fatty acids counteract lipid alterations induced by the core protein. J Hepatol 54(3):432–438

    Article  CAS  PubMed  Google Scholar 

  • Mohankumar KM, Xu XQ, Zhu T, Kannan N, Miller LD, Liu ET, Gluckman PD, Sukumar S, Emerald BS, Lobie PE (2007) HOXA1-stimulated oncogenicity is mediated by selective upregulation of components of the p44/42 MAP kinase pathway in human mammary carcinoma cells. Oncogene 26(27):3998–4008

    Article  CAS  PubMed  Google Scholar 

  • Moriishi K, Matsuura Y (2012) Exploitation of lipid components by viral and host proteins for hepatitis C virus infection. Front Microbiol 3:54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moriishi K, Okabayashi T, Nakai K, Moriya K, Koike K, Murata S, Chiba T, Tanaka K, Suzuki R, Suzuki T, Miyamura T, Matsuura Y (2003) Proteasome activator PA28gamma-dependent nuclear retention and degradation of hepatitis C virus core protein. J Virol 77(19):10237–10249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moriishi K, Mochizuki R, Moriya K, Miyamoto H, Mori Y, Abe T, Murata S, Tanaka K, Miyamura T, Suzuki T, Koike K, Matsuura Y (2007) Critical role of PA28gamma in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis. Proc Natl Acad Sci U S A 104(5):1661–1666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moriya K, Yotsuyanagi H, Shintani Y, Fujie H, Ishibashi K, Matsuura Y, Miyamura T, Koike K (1997) Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol 78(Pt 7):1527–1531

    Article  CAS  PubMed  Google Scholar 

  • Moriya K, Fujie H, Shintani Y, Yotsuyanagi H, Tsutsumi T, Ishibashi K, Matsuura Y, Kimura S, Miyamura T, Koike K (1998) The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 4(9):1065–1067

    Article  CAS  PubMed  Google Scholar 

  • Moriya K, Nakagawa K, Santa T, Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Miyazawa T, Ishibashi K, Horie T, Imai K, Todoroki T, Kimura S, Koike K (2001) Oxidative stress in the absence of inflammation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis. Cancer Res 61(11):4365–4670

    CAS  PubMed  Google Scholar 

  • Mukherjee A, Shrivastava S, Bhanja Chowdhury J, Ray R, Ray RB (2014) Transcriptional suppression of miR-181c by hepatitis C virus enhances homeobox A1 expression. J Virol 88(14):7929–7940

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nakajima A, Komazawa-Sakon S, Takekawa M, Sasazuki T, Yeh WC, Yagita H, Okumura K, Nakano H (2006) An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway. EMBO J 25(23):5549–5559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Negro F (2010) Hepatitis C virus-induced steatosis: an overview. Dig Dis 28(1):294–299

    Article  PubMed  CAS  Google Scholar 

  • Nemeth E, Ganz T (2006) Regulation of iron metabolism by hepcidin. Annu Rev Nutr 26:323–342

    Article  CAS  PubMed  Google Scholar 

  • Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306(5704):2090–2093

    Article  CAS  PubMed  Google Scholar 

  • Nemeth E, Preza GC, Jung CL, Kaplan J, Waring AJ, Ganz T (2006) The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study. Blood 107(1):328–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nielsen SU, Bassendine MF, Burt AD, Martin C, Pumeechockchai W, Toms GL (2006) Association between hepatitis C virus and very-low-density lipoprotein (VLDL)/LDL analyzed in iodixanol density gradients. J Virol 80(5):2418–2428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishina S, Hino K, Korenaga M, Vecchi C, Pietrangelo A, Mizukami Y, Furutani T, Sakai A, Okuda M, Hidaka I, Okita K, Sakaida I (2008) Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology 134(1):226–238

    Article  CAS  PubMed  Google Scholar 

  • Nunez O, Fernandez-Martinez A, Majano PL, Apolinario A, Gomez-Gonzalo M, Benedicto I, Lopez-Cabrera M, Bosca L, Clemente G, Garcia-Monzon C, Martin-Sanz P (2004) Increased intrahepatic cyclooxygenase 2, matrix metalloproteinase 2, and matrix metalloproteinase 9 expression is associated with progressive liver disease in chronic hepatitis C virus infection: role of viral core and NS5A proteins. Gut 53(11):1665–1672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ogino T, Fukuda H, Imajoh-Ohmi S, Kohara M, Nomoto A (2004) Membrane binding properties and terminal residues of the mature hepatitis C virus capsid protein in insect cells. J Virol 78(21):11766–11777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okada S (1996) Iron-induced tissue damage and cancer: the role of reactive oxygen species-free radicals. Pathol Int 46(5):311–332

    Article  CAS  PubMed  Google Scholar 

  • Okamoto K, Moriishi K, Miyamura T, Matsuura Y (2004) Intramembrane proteolysis and endoplasmic reticulum retention of hepatitis C virus core protein. J Virol 78(12):6370–6380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okamoto K, Mori Y, Komoda Y, Okamoto T, Okochi M, Takeda M, Suzuki T, Moriishi K, Matsuura Y (2008) Intramembrane processing by signal peptide peptidase regulates the membrane localization of hepatitis C virus core protein and viral propagation. J Virol 82(17):8349–8361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okuda M, Li K, Beard MR, Showalter LA, Scholle F, Lemon SM, Weinman SA (2002) Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology 122(2):366–375

    Article  CAS  PubMed  Google Scholar 

  • Olynyk JK, Reddy KR, Di Bisceglie AM, Jeffers LJ, Parker TI, Radick JL, Schiff ER, Bacon BR (1995) Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology 108(4):1104–1109

    Article  CAS  PubMed  Google Scholar 

  • Pantopoulos K, Porwal SK, Tartakoff A, Devireddy L (2012) Mechanisms of mammalian iron homeostasis. Biochemistry 51(29):5705–5724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parvanova I, Epiphanio S, Fauq A, Golde TE, Prudencio M, Mota MM (2009) A small molecule inhibitor of signal peptide peptidase inhibits Plasmodium development in the liver and decreases malaria severity. PLoS One 4(4):e5078

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pazienza V, Clement S, Pugnale P, Conzelman S, Foti M, Mangia A, Negro F (2007) The hepatitis C virus core protein of genotypes 3a and 1b downregulates insulin receptor substrate 1 through genotype-specific mechanisms. Hepatology 45(5):1164–1171

    Article  CAS  PubMed  Google Scholar 

  • Perlemuter G, Sabile A, Letteron P, Vona G, Topilco A, Chretien Y, Koike K, Pessayre D, Chapman J, Barba G, Brechot C (2002) Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion: a model of viral-related steatosis. FASEB J 16(2):185–194

    Article  CAS  PubMed  Google Scholar 

  • Persico M, Capasso M, Persico E, Svelto M, Russo R, Spano D, Croce L, La Mura V, Moschella F, Masutti F, Torella R, Tiribelli C, Iolascon A (2007) Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: insulin resistance and response to antiviral therapy. Hepatology 46(4):1009–1015

    Article  CAS  PubMed  Google Scholar 

  • Piccoli C, Scrima R, Quarato G, D'Aprile A, Ripoli M, Lecce L, Boffoli D, Moradpour D, Capitanio N (2007) Hepatitis C virus protein expression causes calcium-mediated mitochondrial bioenergetic dysfunction and nitro-oxidative stress. Hepatology 46(1):58–65

    Article  CAS  PubMed  Google Scholar 

  • Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, Weiner AJ, Houghton M, Rosa D, Grandi G, Abrignani S (1998) Binding of hepatitis C virus to CD81. Science 282(5390):938–941

    Article  CAS  PubMed  Google Scholar 

  • Ploss A, Evans MJ, Gaysinskaya VA, Panis M, You H, de Jong YP, Rice CM (2009) Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 457(7231):882–886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pohlmann S, Zhang J, Baribaud F, Chen Z, Leslie GJ, Lin G, Granelli-Piperno A, Doms RW, Rice CM, McKeating JA (2003) Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR. J Virol 77(7):4070–4080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rouschop KM, van den Beucken T, Dubois L, Niessen H, Bussink J, Savelkouls K, Keulers T, Mujcic H, Landuyt W, Voncken JW, Lambin P, van der Kogel AJ, Koritzinsky M, Wouters BG (2010) The unfolded protein response protects human tumor cells during hypoxia through regulation of the autophagy genes MAP1LC3B and ATG5. J Clin Invest 120(1):127–141

    Article  CAS  PubMed  Google Scholar 

  • Rui L, Aguirre V, Kim JK, Shulman GI, Lee A, Corbould A, Dunaif A, White MF (2001) Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest 107(2):181–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rui L, Yuan M, Frantz D, Shoelson S, White MF (2002) SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J Biol Chem 277(44):42394–42398

    Article  CAS  PubMed  Google Scholar 

  • Saeed M, Suzuki R, Watanabe N, Masaki T, Tomonaga M, Muhammad A, Kato T, Matsuura Y, Watanabe H, Wakita T, Suzuki T (2011) Role of the endoplasmic reticulum-associated degradation (ERAD) pathway in degradation of hepatitis C virus envelope proteins and production of virus particles. J Biol Chem 286(43):37264–37273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shavinskaya A, Boulant S, Penin F, McLauchlan J, Bartenschlager R (2007) The lipid droplet binding domain of hepatitis C virus core protein is a major determinant for efficient virus assembly. J Biol Chem 282(51):37158–37169

    Article  CAS  PubMed  Google Scholar 

  • Shintani Y, Fujie H, Miyoshi H, Tsutsumi T, Tsukamoto K, Kimura S, Moriya K, Koike K (2004) Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology 126(3):840–848

    Article  CAS  PubMed  Google Scholar 

  • Shirakura M, Murakami K, Ichimura T, Suzuki R, Shimoji T, Fukuda K, Abe K, Sato S, Fukasawa M, Yamakawa Y, Nishijima M, Moriishi K, Matsuura Y, Wakita T, Suzuki T, Howley PM, Miyamura T, Shoji I (2007) E6AP ubiquitin ligase mediates ubiquitylation and degradation of hepatitis C virus core protein. J Virol 81(3):1174–1185

    Article  CAS  PubMed  Google Scholar 

  • Shukla R, Upton KR, Munoz-Lopez M, Gerhardt DJ, Fisher ME, Nguyen T, Brennan PM, Baillie JK, Collino A, Ghisletti S, Sinha S, Iannelli F, Radaelli E, Dos Santos A, Rapoud D, Guettier C, Samuel D, Natoli G, Carninci P, Ciccarelli FD, Garcia-Perez JL, Faivre J, Faulkner GJ (2013) Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell 153(1):101–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singaravelu R, Chen R, Lyn RK, Jones DM, O'Hara S, Rouleau Y, Cheng J, Srinivasan P, Nasheri N, Russell RS, Tyrrell DL, Pezacki JP (2014) Hepatitis C virus induced up-regulation of microRNA-27: a novel mechanism for hepatic steatosis. Hepatology 59(1):98–108

    Article  CAS  PubMed  Google Scholar 

  • Solinas G, Karin M (2010) JNK1 and IKKbeta: molecular links between obesity and metabolic dysfunction. FASEB J Off Publ Fed Am Soc Exp Biol 24(8):2596–2611

    CAS  Google Scholar 

  • Tai AW, Benita Y, Peng LF, Kim SS, Sakamoto N, Xavier RJ, Chung RT (2009) A functional genomic screen identifies cellular cofactors of hepatitis C virus replication. Cell Host Microbe 5(3):298–307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanaka N, Moriya K, Kiyosawa K, Koike K, Gonzalez FJ, Aoyama T (2008) PPARalpha activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice. J Clin Invest 118(2):683–694

    PubMed  PubMed Central  Google Scholar 

  • Tanaka T, Kasai H, Yamashita A, Okuyama-Dobashi K, Yasumoto J, Maekawa S, Enomoto N, Okamoto T, Matsuura Y, Morimatsu M, Manabe N, Ochiai K, Yamashita K, Moriishi K (2014) Hallmarks of hepatitis C virus in equine hepacivirus. J Virol in press. doi:10.1128/JVI.02280-02214

  • Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7(2):85–96

    Article  CAS  PubMed  Google Scholar 

  • Targett-Adams P, Schaller T, Hope G, Lanford RE, Lemon SM, Martin A, McLauchlan J (2006) Signal peptide peptidase cleavage of GB virus B core protein is required for productive infection in vivo. J Biol Chem 281(39):29221–29227

    Article  CAS  PubMed  Google Scholar 

  • Theurl I, Zoller H, Obrist P, Datz C, Bachmann F, Elliott RM, Weiss G (2004) Iron regulates hepatitis C virus translation via stimulation of expression of translation initiation factor 3. J Infect Dis 190(4):819–825

    Article  CAS  PubMed  Google Scholar 

  • Thirone AC, Huang C, Klip A (2006) Tissue-specific roles of IRS proteins in insulin signaling and glucose transport. Trends Endocrinol Metab TEM 17(2):72–78

    Article  PubMed  CAS  Google Scholar 

  • Thomssen R, Bonk S, Propfe C, Heermann KH, Kochel HG, Uy A (1992) Association of hepatitis C virus in human sera with beta-lipoprotein. Med Microbiol Immunol 181(5):293–300

    Article  CAS  PubMed  Google Scholar 

  • Thomssen R, Bonk S, Thiele A (1993) Density heterogeneities of hepatitis C virus in human sera due to the binding of beta-lipoproteins and immunoglobulins. Med Microbiol Immunol 182(6):329–334

    Article  CAS  PubMed  Google Scholar 

  • Tsutsumi T, Suzuki T, Moriya K, Yotsuyanagi H, Shintani Y, Fujie H, Matsuura Y, Kimura S, Koike K, Miyamura T (2002a) Alteration of intrahepatic cytokine expression and AP-1 activation in transgenic mice expressing hepatitis C virus core protein. Virology 304(2):415–424

    Article  CAS  PubMed  Google Scholar 

  • Tsutsumi T, Suzuki T, Shimoike T, Suzuki R, Moriya K, Shintani Y, Fujie H, Matsuura Y, Koike K, Miyamura T (2002b) Interaction of hepatitis C virus core protein with retinoid X receptor alpha modulates its transcriptional activity. Hepatology 35(4):937–946

    Article  CAS  PubMed  Google Scholar 

  • Tsutsumi T, Matsuda M, Aizaki H, Moriya K, Miyoshi H, Fujie H, Shintani Y, Yotsuyanagi H, Miyamura T, Suzuki T, Koike K (2009) Proteomics analysis of mitochondrial proteins reveals overexpression of a mitochondrial protein chaperon, prohibitin, in cells expressing hepatitis C virus core protein. Hepatology 50(2):378–386

    Article  CAS  PubMed  Google Scholar 

  • Ueki K, Kondo T, Kahn CR (2004) Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24(12):5434–5446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang RH, Li C, Xu X, Zheng Y, Xiao C, Zerfas P, Cooperman S, Eckhaus M, Rouault T, Mishra L, Deng CX (2005) A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab 2(6):399–409

    Article  CAS  PubMed  Google Scholar 

  • Wang Q, Liu Y, An D, Diao H, Xu W, He X, Sun R, Wei L, Li L (2012) Regulation of hepatitis C virus translation initiation by iron: role of eIF3 and La protein. Virus Res 167(2):302–309

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Kang R, Huang H, Xi X, Wang B, Wang J, Zhao Z (2014) Hepatitis C virus core protein activates autophagy through EIF2AK3 and ATF6 UPR pathway-mediated MAP1LC3B and ATG12 expression. Autophagy 10(5):766–784

    Article  CAS  PubMed  Google Scholar 

  • Waris G, Felmlee DJ, Negro F, Siddiqui A (2007) Hepatitis C virus induces proteolytic cleavage of sterol regulatory element binding proteins and stimulates their phosphorylation via oxidative stress. J Virol 81(15):8122–8130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Werner ED, Lee J, Hansen L, Yuan M, Shoelson SE (2004) Insulin resistance due to phosphorylation of insulin receptor substrate-1 at serine 302. J Biol Chem 279(34):35298–35305

    Article  CAS  PubMed  Google Scholar 

  • Wu CF, Lin YL, Huang YT (2013) Hepatitis C virus core protein stimulates fibrogenesis in hepatic stellate cells involving the obese receptor. J Cell Biochem 114(3):541–550

    Article  CAS  PubMed  Google Scholar 

  • Xia Y, Babitt JL, Sidis Y, Chung RT, Lin HY (2008) Hemojuvelin regulates hepcidin expression via a selective subset of BMP ligands and receptors independently of neogenin. Blood 111(10):5195–5204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamaguchi A, Tazuma S, Nishioka T, Ohishi W, Hyogo H, Nomura S, Chayama K (2005) Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver. Dig Dis Sci 50(7):1361–1371

    Article  CAS  PubMed  Google Scholar 

  • Youngren JF (2007) Regulation of insulin receptor function. Cell Mol Life Sci: CMLS 64(7–8):873–891

    Article  CAS  PubMed  Google Scholar 

  • Yu S, Matsusue K, Kashireddy P, Cao WQ, Yeldandi V, Yeldandi AV, Rao MS, Gonzalez FJ, Reddy JK (2003) Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1) overexpression. J Biol Chem 278(1):498–505

    Article  CAS  PubMed  Google Scholar 

  • Zhang M, Gaschen B, Blay W, Foley B, Haigwood N, Kuiken C, Korber B (2004) Tracking global patterns of N-linked glycosylation site variation in highly variable viral glycoproteins: HIV, SIV, and HCV envelopes and influenza hemagglutinin. Glycobiology 14(12):1229–1246

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yoshiharu Matsuura D.V.M., Ph.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Japan

About this chapter

Cite this chapter

Moriishi, K., Matsuura, Y. (2016). Structural Proteins of HCV and Biological Functions. In: Miyamura, T., Lemon, S., Walker, C., Wakita, T. (eds) Hepatitis C Virus I. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56098-2_6

Download citation

Publish with us

Policies and ethics