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The functional role of sodium taurocholate cotransporting polypeptide NTCP in the life cycle of hepatitis B, C and D viruses

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Abstract

Chronic hepatitis B, C and D virus (HBV, HCV and HDV) infections are a major cause of liver disease and cancer worldwide. Despite employing distinct replication strategies, the three viruses are exclusively hepatotropic, and therefore depend on hepatocyte-specific host factors. The sodium taurocholate co-transporting polypeptide (NTCP), a transmembrane protein highly expressed in human hepatocytes that mediates the transport of bile acids, plays a key role in HBV and HDV entry into hepatocytes. Recently, NTCP has been shown to modulate HCV infection of hepatocytes by regulating innate antiviral immune responses in the liver. Here, we review the current knowledge of the functional role and the molecular and cellular biology of NTCP in the life cycle of the three major hepatotropic viruses, highlight the impact of NTCP as an antiviral target and discuss future avenues of research.

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References

  1. World Health Organization (2016) Global health sector strategy on viral hepatitis 2016–2021. Towards ending viral hepatitis. World Health Organization. http://www.who.int/iris/handle/10665/246177

  2. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ (2015) Estimations of worldwide prevalence of chronic hepatitis B virus infection: A systematic review of data published between 1965 and 2013. Lancet 386:1546–1555. https://doi.org/10.1016/S0140-6736(15)61412-X

    Article  PubMed  Google Scholar 

  3. World Health Organization (2017) Global hepatitis report 2017. World Health Organization. License: CC BY-NC-SA 3.0 IGO. http://www.who.int/iris/handle/10665/255016

  4. Sultanik P, Pol S (2016) Hepatitis delta virus: epidemiology, natural course and treatment. J Infect Dis Ther 4:2–7. https://doi.org/10.4172/2332-0877.1000271

    Article  CAS  Google Scholar 

  5. Chung RT, Baumert TF (2014) Curing chronic hepatitis C—the arc of a medical triumph. New Engl J Med 370:1576–1578. https://doi.org/10.1056/NEJMp1401833

    Article  CAS  PubMed  Google Scholar 

  6. Werle-Lapostolle B, Bowden S, Locarnini S, Wursthorn K, Petersen J, Lau G, Trepo C, Marcellin P, Goodman Z, Delaney WE, Xiong S, Brosgart CL, Chen S, Gibbs CS, Zoulim F (2004) Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 126:1750–1758. https://doi.org/10.1053/j.gastro.2004.03.018

    Article  CAS  PubMed  Google Scholar 

  7. Papatheodoridis GV, Idilman R, Dalekos GN, Buti M, Chi H, Van Boemmel F, Calleja JL, Sypsa V, Goulis J, Manolakopoulos S, Loglio A, Siakavellas S, Keskın O, Gatselis N, Hansen BE, Lehretz M, De Revilla J, Savvidou S, Kourikou A, Vlachogiannakos I, Galanis K, Yurdaydin C, Berg T, Colombo M, Esteban R, Janssen HLA, Lampertico P (2017) The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B. Hepatology 66:1444–1453. https://doi.org/10.1002/hep.29320

    Article  CAS  PubMed  Google Scholar 

  8. Baumert TF, Jühling F, Ono A, Hoshida Y (2017) Hepatitis C-related hepatocellular carcinoma in the era of new generation antivirals. BMC Med 15:1–10. https://doi.org/10.1186/s12916-017-0815-7

    Article  CAS  Google Scholar 

  9. Baumert TF, Verrier ER, Nassal M, Chung RT, Zeisel MB (2015) Host-targeting agents for treatment of hepatitis B virus infection. Curr Opin Virol 14:41–46. https://doi.org/10.1016/j.coviro.2015.07.009

    Article  CAS  PubMed  Google Scholar 

  10. Mailly L, Xiao F, Lupberger J, Wilson GK, Aubert P, Duong FHT, Calabrese D, Leboeuf C, Fofana I, Thumann C, Bandiera S, Lütgehetmann M, Volz T, Davis C, Harris HJ, Mee CJ, Girardi E, Chane-Woon-Ming B, Ericsson M, Fletcher N, Bartenschlager R, Pessaux P, Vercauteren K, Meuleman P, Villa P, Kaderali L, Pfeffer S, Heim MH, Neunlist M, Zeisel MB, Dandri M, McKeating JA, Robinet E, Baumert TF (2015) Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody. Nat Biotechnol 33:549–554. https://doi.org/10.1038/nbt.3179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zeisel MB, Baumert TF (2017) Clinical development of hepatitis C virus host-targeting agents. Lancet 389:674–675. https://doi.org/10.1016/S0140-6736(17)30043-0

    Article  PubMed  PubMed Central  Google Scholar 

  12. Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, Huang Y, Qi Y, Peng B, Wang H, Fu L, Song M, Chen P, Gao W, Ren B, Sun Y, Cai T, Feng X, Sui J, Li W (2012) Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 1:e000049. https://doi.org/10.7554/eLife.00049

    Article  CAS  Google Scholar 

  13. Ni Y, Lempp FA, Mehrle S, Nkongolo S, Kaufman C, Fälth M, Stindt J, Königer C, Nassal M, Kubitz R, Sültmann H, Urban S (2014) Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 146:1070–1083. https://doi.org/10.1053/j.gastro.2013.12.024

    Article  CAS  PubMed  Google Scholar 

  14. Volz T, Allweiss L, Ben ḾBarek M, Warlich M, Lohse AW, Pollok JM, Alexandrov A, Urban S, Petersen J, Lütgehetmann M, Dandri M (2013) The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J Hepatol 58:861–867. https://doi.org/10.1016/j.jhep.2012.12.008

    Article  CAS  PubMed  Google Scholar 

  15. Watashi K, Sluder A, Daito T, Matsunaga S, Ryo A, Nagamori S, Iwamoto M, Nakajima S, Tsukuda S, Borroto-Esoda K, Sugiyama M, Tanaka Y, Kanai Y, Kusuhara H, Mizokami M, Wakita T (2014) Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP). Hepatology 59:1726–1737. https://doi.org/10.1002/hep.26982

    Article  CAS  PubMed  Google Scholar 

  16. Nkongolo S, Ni Y, Lempp FA, Kaufman C, Lindner T, Esser-Nobis K, Lohmann V, Mier W, Mehrle S, Urban S (2014) Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor. J Hepatol 60:723–731. https://doi.org/10.1016/j.jhep.2013.11.022

    Article  CAS  PubMed  Google Scholar 

  17. Shimura S, Watashi K, Fukano K, Peel M, Sluder A, Kawai F, Iwamoto M, Tsukuda S, Takeuchi JS, Miyake T, Sugiyama M, Ogasawara Y, Park S, Tanaka Y, Kusuhara H, Mizokami M, Sureau C, Wakita T (2017) Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity. J Hepatol 66:685–692. https://doi.org/10.1016/j.jhep.2016.11.009

    Article  CAS  PubMed  Google Scholar 

  18. Donkers JM, Zehnder B, Van Westen GJP, Kwakkenbos MJ, Ijzerman AP, Elferink RPJO, Beuers U, Urban S, van de Graaf SFJ (2017) Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP. Sci Rep 7:1–13. https://doi.org/10.1038/s41598-017-15338-0

    Article  CAS  Google Scholar 

  19. Kaneko M, Futamura Y, Tsukuda S, Kondoh Y, Sekine T, Hirano H, Fukano K, Ohashi H, Saso W, Morishita R, Matsunaga S, Kawai F, Ryo A, Park S-Y, Suzuki R, Aizaki H, Ohtani N, Sureau C, Wakita T, Osada H, Watashi K (2018) Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide. Sci Rep 8:1–13. https://doi.org/10.1038/s41598-018-20987-w

    Article  CAS  Google Scholar 

  20. Verrier ER, Colpitts CC, Schuster C, Zeisel MB, Baumert TF (2016) Cell culture models for the investigation of Hepatitis B and D Virus infection. Viruses 8:1–10. https://doi.org/10.3390/v8090261

    Article  CAS  Google Scholar 

  21. Döring B, Lütteke T, Geyer J, Petzinger E (2012) The SLC10 carrier family: transport functions and molecular structure. Curr Top Membr 70:105–168. https://doi.org/10.1016/B978-0-12-394316-3.00004-1

    Article  CAS  PubMed  Google Scholar 

  22. Esteller A (2008) Physiology of bile secretion. World J Gastroenterol 14:5641–5649. https://doi.org/10.3748/wjg.14.5641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Podevin P, Rosmorduc O, Conti F, Calmus Y, Meier PJ, Poupon R (1999) Bile acids modulate the interferon signalling pathway. Hepatology 29:1840–1847

    Article  CAS  PubMed  Google Scholar 

  24. Graf D, Haselow K, Münks I, Bode JG, Häussinger D (2010) Inhibition of interferon-a-induced signaling by hyperosmolarity and hydrophobic bile acids. Biol Chem 391:1175–1187. https://doi.org/10.1515/BC.2010.108

    Article  CAS  PubMed  Google Scholar 

  25. Slijepcevic D, van de Graaf FJ (2017) Bile acid uptake transporters as targets for therapy. Dig Dis 35:251–258. https://doi.org/10.1159/000450983

    Article  PubMed  Google Scholar 

  26. Geyer J, Wilke T, Petzinger E (2006) The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships. Naunyn-Schmiedeberg’s Arch Pharmacol 372:413–431. https://doi.org/10.1007/s00210-006-0043-8

    Article  CAS  Google Scholar 

  27. Hagenbuch B, Meier PJ (1994) Molecular cloning, chromosomal localization, and functional characterization of a human liver Na +/bile acid cotransporter. J Clin Invest 93:1326–1331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mukhopadhyay S, Ananthanarayanan M, Stieger B, Meier PJ, Suchy FJ, Anwer MS (1998) Sodium taurocholate cotransporting polypeptide is a serine, threonine phosphoprotein and is dephosphorylated by cyclic adenosine monophosphate. Hepatology 92:1629–1636

    Article  Google Scholar 

  29. da Silva TC, Polli JE, Swaan PW (2013) The solute carrier family 10 (SLC10): beyond bile acid transport. Mol Aspects Med 34:252–269. https://doi.org/10.1016/j.mam.2012.07.004.The

    Article  PubMed Central  Google Scholar 

  30. Hu N-J, Iwata S, Cameron AD, Drew D (2011) Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT. Nature 478:408–411. https://doi.org/10.1038/nature10450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Dawson PA (2011) Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol 201:169–203. https://doi.org/10.1007/978-3-642-14541-4

    Article  CAS  Google Scholar 

  32. Dong Z, Ekins S, Polli JE (2013) Structure activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate co-transporting polypeptide (NTCP). Mol Pharm 10:1008–1019. https://doi.org/10.1021/mp300453k.Structure

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chiang JYL (2003) Bile acid regulation of hepatic physiology III. Bile acids and nuclear receptors. Am J Physiol Gastrointest Liver Physiol 284:G349–G356

    Article  CAS  PubMed  Google Scholar 

  34. Goodwin B, Jones SA, Price RR, Watson MA, Mckee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, Maloney PR, Willson TM, Kliewer SA (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6:517–526

    Article  CAS  PubMed  Google Scholar 

  35. Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6:507–515

    Article  CAS  PubMed  Google Scholar 

  36. Jonker JW, Stedman CAM, Liddle C, Downes M (2009) Hepatobiliary ABC transporters: physiology, regulation and implications for disease. Front Biosci 14:4904–4920. https://doi.org/10.2741/3576

    Article  CAS  Google Scholar 

  37. Chiang JYL (2009) Bile acids: regulation of synthesis. J Lipid Res 50:1955–1966. https://doi.org/10.1194/jlr.R900010-JLR200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gerloff T, Stieger B, Hagenbuch B, Madon J, Landmann L, Roth J, Hofmann AF, Meier PJ (1998) The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem 273:10046–10050

    Article  CAS  PubMed  Google Scholar 

  39. Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf DJ, Suchy FJ (2001) Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem 276:28857–28865. https://doi.org/10.1074/jbc.M011610200

    Article  CAS  PubMed  Google Scholar 

  40. Denson LA, Sturm E, Echevarria W, Zimmerman TL, Makishima M, Mangelsdorf DJ, Karpen SJ (2001) The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology 121:140–147. https://doi.org/10.1053/gast.2001.25503

    Article  CAS  PubMed  Google Scholar 

  41. Jung D, Hagenbuch B, Fried M, Meier PJ, Kullak-Ublick GA (2004) Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene. Am J Physiol Gastrointest Liver Physiol 286:752–761

    Article  Google Scholar 

  42. Geier A, Martin IV, Dietrich CG, Balasubramaniyan N, Strauch S, Suchy FJ, Gartung C, Trautwein C, Ananthanarayanan M (2008) Hepatocyte nuclear factor-4a is a central transactivator of the mouse Ntcp gene. Am J Physiol Gastrointest Liver Physiol 295:226–233. https://doi.org/10.1152/ajpgi.00012.2008

    Article  CAS  Google Scholar 

  43. Li D, Zimmerman TL, Thevananther S, Lee H-Y, Kurie JM, Karpen SJ (2002) Interleukin-1b-mediated suppression of RXR:RAR transactivation of the Ntcp promoter Is JNK-dependent. J Biol Chem 277:31416–31422. https://doi.org/10.1074/jbc.M204818200

    Article  CAS  PubMed  Google Scholar 

  44. Siewert E, Dietrich CG, Lammert F, Heinrich PC, Matern S, Gartung C, Geier A (2004) Interleukin-6 regulates hepatic transporters during acute-phase response. Biochem Biophys Res Commun 322:232–238. https://doi.org/10.1016/j.bbrc.2004.07.102

    Article  CAS  PubMed  Google Scholar 

  45. Le Vee M, Lecureur V, Stieger B, Fardel O (2009) Regulation of drug transporter expression in human hepatocytes exposed to the proinflammatory cytokines tumor necrosis factor-a or interleukin-6. Drug Metab Dispos 37:685–693. https://doi.org/10.1124/dmd.108.023630.pump

    Article  PubMed  Google Scholar 

  46. Zollner G, Fickert P, Silbert D, Fuchsbichler A, Marschall H-U, Zatloukal K, Denk H, Trauner M (2003) Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 38:717–727. https://doi.org/10.1016/S0168-8278(03)00096-5

    Article  CAS  PubMed  Google Scholar 

  47. Kojima H, Nies AT, König J, Hagmann W, Spring H, Uemura M, Fukui H, Keppler D (2003) Changes in the expression and localization of hepatocellular transporters and radixin in primary biliary cirrhosis. J Hepatol 39:693–702. https://doi.org/10.1016/S0168-8278(03)00410-0

    Article  CAS  PubMed  Google Scholar 

  48. Kang J, Wang J, Cheng J, Cao Z, Chen R, Li H, Liu S, Chen X, Sui J, Lu F (2017) Down-regulation of NTCP expression by cyclin D1 in hepatitis B virus-related hepatocellular carcinoma has clinical significance. Oncotarget 8:56041–56050

    PubMed  Google Scholar 

  49. Anwer MS (2014) Role of protein kinase C isoforms in bile formation and cholestasis. Hepatology 60:1090–1097. https://doi.org/10.1002/hep.27088.Role

    Article  CAS  PubMed  Google Scholar 

  50. Grüne S, Engelking LR, Anwer MS (1993) Role of intracellular calcium and protein kinases in the activation of hepatic Na +/taurocholate cotransport by cyclic AMP. J Biol Chem 268:17734–17741

    PubMed  Google Scholar 

  51. Webster CRL, Blanch C, Anwer MS (2002) Role of PP2B in cAMP-induced dephosphorylation and translocation of NTCP. Am J Physiol Gastrointest Liver Physiol 283:G44–G50

    Article  CAS  PubMed  Google Scholar 

  52. Anwer MS, Gillin H, Mukhopadhyay S, Balasubramaniyan N, Suchy FJ, Ananthanarayanan M (2005) Dephosphorylation of Ser-226 facilitates plasma membrane retention of Ntcp. J Biol Chem 280:33687–33692. https://doi.org/10.1074/jbc.M502151200

    Article  CAS  PubMed  Google Scholar 

  53. Ho RH, Leake BF, Roberts RL, Lee W, Kim RB (2004) Ethnicity-dependent polymorphism in Na+ -taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition. J Biol Chem 279:7213–7222. https://doi.org/10.1074/jbc.M305782200

    Article  CAS  PubMed  Google Scholar 

  54. Pan W, Song I-S, Shin H-J, Kim M-H, Choi Y-L, Lim J, Kim W-Y, Lee S-S, Shin J-G (2011) Genetic polymorphisms in Na+ -taurocholate co-transporting polypeptide (NTCP) and ileal apical sodium-dependent bile acid transporter (ASBT) and ethnic comparisons of functional variants of NTCP among Asian populations. Xenobiotica 41:501–510. https://doi.org/10.3109/00498254.2011.555567

    Article  CAS  PubMed  Google Scholar 

  55. Sureau C, Guerra B, Lanford RE (1993) Role of the large hepatitis B virus envelope protein in infectivity of the hepatitis delta virion. J Virol 67:366–372

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Nassal M (2015) HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 64:1972–1984. https://doi.org/10.1136/gutjnl-2015-309809

    Article  CAS  PubMed  Google Scholar 

  57. Lucifora J, Protzer U (2016) Attacking hepatitis B virus cccDNA—the holy grail to hepatitis B cure. J Hepatol 64:S41–S48. https://doi.org/10.1016/j.jhep.2016.02.009

    Article  CAS  PubMed  Google Scholar 

  58. Rizzetto M, Hoyer B, Canese MG, Shih JW, Purcellt RH, Gerin JL (1980) Delta agent: association of delta antigen with hepatitis B surface antigen and RNA in serum of delta-infected chimpanzees. PNAS 77:6124–6128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sureau C, Negro F (2016) The hepatitis delta virus: replication and pathogenesis. J Hepatol 64:S102–S116. https://doi.org/10.1016/j.jhep.2016.02.013

    Article  CAS  PubMed  Google Scholar 

  60. Marsh M, Helenius A (2006) Virus entry: open sesame. Cell 124:729–740. https://doi.org/10.1016/j.cell.2006.02.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Abou Jaoude G, Sureau C (2005) Role of the antigenic loop of the hepatitis B virus envelope proteins in infectivity of hepatitis delta virus. J Virol 79:10460–10466. https://doi.org/10.1128/JVI.79.16.10460

    Article  Google Scholar 

  62. Abou Jaoude G, Sureau C (2007) Entry of hepatitis delta virus requires the conserved cysteine residues of the hepatitis B virus envelope protein antigenic loop and is blocked by inhibitors of thiol-disulfide exchange. J Virol 81:13057–13066. https://doi.org/10.1128/JVI.01495-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Persing DH, Varmus HE, Ganem DON (1987) The preS1 protein of hepatitis B virus is acylated at its amino terminus with myristic acid. J Virol 61:1672–1677

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Gripon P, Seyec JLE, Rumin S, Guguen-Guillouzo C (1995) Myristylation of the hepatitis B virus large surface protein is essential for viral infectivity. Virology 213:292–299

    Article  CAS  PubMed  Google Scholar 

  65. Bruss V, Hagelstein J, Gerhardt E, Galle PR (1996) Myristylation of the large surface protein is required for hepatitis B virus in vitro infectivity. Virology 218:396–399

    Article  CAS  PubMed  Google Scholar 

  66. Gripon P, Rumin S, Urban S, Le Seyec J, Glaise D, Cannie I, Guyomard C, Lucas J, Trepo C, Guguen-Guillouzo C (2002) Infection of a human hepatoma cell line by hepatitis B virus. Proc Natl Acad Sci USA. 99:15655–15660. https://doi.org/10.1073/pnas.232137699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Spillmann D (2001) Heparan sulfate: Anchor for viral intruders? Biochimie 83:811–817

    Article  CAS  PubMed  Google Scholar 

  68. Bartlett AH, Park PW (2015) Proteoglycans in host–pathogen interactions: molecular mechanisms and therapeutic implications. Expert Rev Mol Med 12:e5. https://doi.org/10.1017/S1462399409001367

    Article  CAS  Google Scholar 

  69. Schulze A, Gripon P, Urban S (2007) Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans. Hepatology 46:1759–1768. https://doi.org/10.1002/hep.21896

    Article  CAS  PubMed  Google Scholar 

  70. Sureau C, Salisse J (2013) A conformational heparan sulfate binding site essential to infectivity overlaps with the conserved hepatitis B virus a-determinant. Hepatology 57:985–994. https://doi.org/10.1002/hep.26125

    Article  CAS  PubMed  Google Scholar 

  71. Verrier ER, Colpitts CC, Bach C, Heydmann L, Weiss A, Renaud M, Durand SC, Habersetzer F, Durantel D, Abou-Jaoudé G, López Ledesma MM, Felmlee DJ, Soumillon M, Croonenborghs T, Pochet N, Nassal M, Schuster C, Brino L, Sureau C, Zeisel MB, Baumert TF (2016) A targeted functional RNA interference screen uncovers glypican 5 as an entry factor for hepatitis B and D viruses. Hepatology 63:35–48. https://doi.org/10.1002/hep.28013

    Article  CAS  PubMed  Google Scholar 

  72. Leistner CM, Gruen-Bernhard S, Glebe D (2008) Role of glycosaminoglycans for binding and infection of hepatitis B virus. Cell Microbiol 10:122–133. https://doi.org/10.1111/j.1462-5822.2007.01023.x

    Article  CAS  PubMed  Google Scholar 

  73. Neurath AR, Kent SBH, Strick N, Parker K (1986) Identification and chemical synthesis of a host cell receptor binding site on hepatitis B virus. Cell 46:429–436

    Article  CAS  PubMed  Google Scholar 

  74. Neurath BAR, Strick N, Sproul P (1992) Search for hepatitis B virus cell receptors reveals binding sites for interleukin 6 on the virus envelope protein. J Exp Med 175:461–469

    Article  CAS  PubMed  Google Scholar 

  75. Pontisso P, Ruvoletto MG, Tiribelli C, Gerlich WH, Ruop A, Alberti A (1992) The preS1 domain of hepatitis B virus and IgA cross-react in their binding to the hepatocyte surface. J Gen Virol 73:2041–2045

    Article  CAS  PubMed  Google Scholar 

  76. Ryu CJ, Cho D, Gripon P, Kim HS, Guguen-Guillouzo C, Hong HJ (2000) An 80-kilodalton protein that binds to the Pre-S1 domain of hepatitis B virus. J Virol 74:110–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. De Falco S, Ruvoletto MG, Verdoliva A, Ruvo M, Raucci A, Marino M, Senatore S, Cassani G, Alberti A, Pontisso P, Fassina G (2001) Cloning and expression of a novel hepatitis B virus-binding protein from HepG2 cells. J Biol Chem 276:36613–36623. https://doi.org/10.1074/jbc.M102377200

    Article  Google Scholar 

  78. Li D, Wang XZ, Ding J, Yu J-P (2005) NACA as a potential cellular target of hepatitis B virus PreS1 protein. Dig Dis Sci 50:1156–1160. https://doi.org/10.1007/s10620-005-2724-4

    Article  CAS  PubMed  Google Scholar 

  79. Zhong G, Yan H, Wang H, He W, Jing Z, Qi Y, Fu L, Gao Z, Huang Y, Xu G, Feng X, Sui J, Li W (2013) Sodium taurocholate cotransporting polypeptide mediates woolly monkey hepatitis B virus infection of tupaia hepatocytes. J Virol 87:7176–7184. https://doi.org/10.1128/JVI.03533-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Peng L, Zhao Q, Li Q, Li M, Li C, Xu T, Jing X, Zhu X, Wang Y, Li F, Liu R, Zhong C, Pan Q, Zeng B, Liao Q, Hu B, Hu Z, Huang Y, Sham P, Liu J, Xu S, Wang J, Gao Z, Wang Y (2015) The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B. Hepatology 61:1251–1260. https://doi.org/10.1002/hep.27608

    Article  CAS  PubMed  Google Scholar 

  81. Lee HW, Park HJ, Jin B, Dezhbord M, Kim DY, Han KH, Ryu WS, Kim S, Ahn SH (2017) Effect of S267F variant of NTCP on the patients with chronic hepatitis B. Sci Rep 7:1–7. https://doi.org/10.1038/s41598-017-17959-x

    Article  Google Scholar 

  82. An P, Zeng Z, Winkler CA (2018) The loss-of-function S267F variant in HBV receptor NTCP reduces human risk to HBV infection and disease progression. J Infect Dis. https://doi.org/10.1093/infdis/jiy355/5037696

    Article  PubMed  PubMed Central  Google Scholar 

  83. Hu H, Liu J, Lin Y-L, Luo W, Chu Y-J, Chang C-L, Jen C-L, Lee M-H, Lu S-N, Wang L-Y, You S-L, Yang H-I, Chen C-J (2016) The rs2296651 (S267F) variant on NTCP (SLC10A1) is inversely associated with chronic hepatitis B and progression to cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B. Gut 65:1514–1521. https://doi.org/10.1136/gutjnl-2015-310686

    Article  CAS  PubMed  Google Scholar 

  84. Zollner G, Wagner M, Fickert P, Silbert D, Fuchsbichler A, Zatloukal K, Denk H, Trauner M (2005) Hepatobiliary transporter expression in human hepatocellular carcinoma. Liver Int 25:367–379. https://doi.org/10.1111/j.1478-3231.2005.01033.x

    Article  CAS  PubMed  Google Scholar 

  85. Gripon P, Diot C, Theze N, Fourel I, Loreal O, Brechot C, Guguen-Guillouzo C (1988) Hepatitis B virus infection of adult human hepatocytes cultured in the presence of dimethyl sulfoxide. J Virol 62:4136–4143

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Lempp FA, Wiedtke E, Qu B, Roques P, Chemin I, Vondran FWR, Le Grand R, Grimm D, Urban S (2017) Sodium taurocholate cotransporting polypeptide is the limiting host factor of hepatitis B virus infection in macaque and pig hepatocytes. Hepatology 66:703–716

    Article  CAS  PubMed  Google Scholar 

  87. Allweiss L, Dandri M (2016) Experimental in vitro and in vivo models for the study of human hepatitis B virus infection. J Hepatol 64:S17–S31. https://doi.org/10.1016/j.jhep.2016.02.012

    Article  CAS  PubMed  Google Scholar 

  88. He W, Ren B, Mao F, Jing Z, Li Y, Liu Y, Peng B, Yan H, Qi Y, Sun Y, Guo J-T, Sui J, Wang F, Li W (2015) Hepatitis D virus infection of mice expressing human sodium taurocholate co-transporting polypeptide. PLoS Pathog 11:1–17. https://doi.org/10.1371/journal.ppat.1004840

    Article  CAS  Google Scholar 

  89. Lempp FA, Mutz P, Lipps C, Wirth D, Bartenschlager R, Urban S (2016) Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor. J Hepatol 64:556–564. https://doi.org/10.1016/j.jhep.2015.10.030

    Article  CAS  PubMed  Google Scholar 

  90. Burwitz BJ, Wettengel JM, Mück-Häusl MA, Ringelhan M, Ko C, Festag MM, Hammond KB, Northrup M, Bimber BN, Jacob T, Reed JS, Norris R, Park B, Moller-Tank S, Esser K, Greene JM, Wu HL, Abdulhaqq S, Webb G, Sutton WF, Klug A, Swanson T, Legasse AW, Vu TQ, Asokan A, Haigwood NL, Protzer U, Sacha JB (2017) Hepatocytic expression of human sodium-taurocholate cotransporting polypeptide enables hepatitis B virus infection of macaques. Nat Commun 8:1–10. https://doi.org/10.1038/s41467-017-01953-y

    Article  CAS  Google Scholar 

  91. Gripon P, Cannie I, Urban S (2005) Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein. J Virol 79:1613–1622. https://doi.org/10.1128/JVI.79.3.1613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Petersen J, Dandri M, Mier W, Lütgehetmann M, Volz T, von Weizsäcker F, Haberkorn U, Fischer L, Pollok J-M, Erbes B, Seitz S, Urban S (2008) Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol 26:335–341. https://doi.org/10.1038/nbt1389

    Article  CAS  PubMed  Google Scholar 

  93. Blank A, Markert C, Hohmann N, Carls A, Mikus G, Lehr T, Alexandrov A, Haag M, Schwab M, Urban S, Haefeli WE (2016) First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol 65:483–489. https://doi.org/10.1016/j.jhep.2016.04.013

    Article  CAS  PubMed  Google Scholar 

  94. Bogomolov P, Alexandrov A, Voronkova N, Macievich M, Kokina K, Petrachenkova M, Lehr T, Lempp FA, Wedemeyer H, Haag M, Schwab M, Haefeli WE, Blank A, Urban S (2016) Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol 65:490–498. https://doi.org/10.1016/j.jhep.2016.04.016

    Article  CAS  PubMed  Google Scholar 

  95. Wedemeyer H, Bogomolov P, Blank A, Allweiss L, Dandri-Petersen M, Bremer B, Voronkova N, Schöneweis K, Pathil A, Burhenne J, Haag M, Schwab M, Haefeli W-E, Wiesch JSZ, Alexandrov A, Urban S (2018) Final results of a multicenter, open-label phase 2b clinical trial to assess safety and efficacy of Myrcludex B in combination with Tenofovir in patients with chronic HBV/HDV co-infection. J Hepatol 68:S3

    Article  Google Scholar 

  96. König A, Döring B, Mohr C, Geipel A, Geyer J, Glebe D (2014) Kinetics of the bile acid transporter and hepatitis B virus receptor Na +/taurocholate cotransporting polypeptide (NTCP) in hepatocytes. J Hepatol 61:867–875. https://doi.org/10.1016/j.jhep.2014.05.018

    Article  CAS  PubMed  Google Scholar 

  97. Blanchet M, Sureau C, Labonté P (2014) Use of FDA approved therapeutics with hNTCP metabolic inhibitory properties to impair the HDV lifecycle. Antivir Res 106:111–115. https://doi.org/10.1016/j.antiviral.2014.03.017

    Article  CAS  PubMed  Google Scholar 

  98. Lucifora J, Esser K, Protzer U (2013) Ezetimibe blocks hepatitis B virus infection after virus uptake into hepatocytes. Antivir Res 97:195–197. https://doi.org/10.1016/j.antiviral.2012.12.008

    Article  CAS  PubMed  Google Scholar 

  99. Azer SA, Stacey H (1993) Differential effects of Cyclosporin A on the transport of bile acids by human hepatocytes. Biochem Pharmacol 46:813–819

    Article  CAS  PubMed  Google Scholar 

  100. Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF, Sugiyama Y (2006) Inhibition of bile acid transport across Na +/taurocholate cotransporting polypeptide (SLC10A1) and bile salt export pump (ABCB 11)-coexpressing LLC-PK1 cells by cholestasis-inducing drugs. Drug Metab Dispos 34:1575–1581. https://doi.org/10.1124/dmd.105.008748.basolateral

    Article  CAS  PubMed  Google Scholar 

  101. Slijepcevic D, Kaufman C, Wichers CGK, Gilglioni EH, Lempp FA, Duijst S, de Waart DR, Oude Elferink RPJ, Mier W, Stieger B, Beuers U, Urban S, van de Graaf SFJ (2015) Impaired uptake of conjugated bile acids and hepatitis B virus Pres1-binding in Na+ -taurocholate cotransporting polypeptide knockout mice. Hepatology 62:207–219. https://doi.org/10.1002/hep.27694

    Article  CAS  PubMed  Google Scholar 

  102. Vaz M, Paulusma CC, Huidekoper H, De RuM, Lim C, Koster J, Ho-Mok K, Bootsma AH, Groen AK, Schaap FG, Oude Elferink RPJ, Waterham HR, Wanders RJA (2015) Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype. Hepatology 61:260–267. https://doi.org/10.1002/hep.27240

    Article  CAS  PubMed  Google Scholar 

  103. Tsukuda S, Watashi K, Hojima T, Isogawa M, Iwamoto M, Omagari K, Suzuki R, Aizaki H, Kojima S, Sugiyama M, Saito A, Tanaka Y, Mizokami M, Sureau C, Wakita T (2017) A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins. Hepatology 65:1104–1116. https://doi.org/10.1002/hep.28952

    Article  CAS  PubMed  Google Scholar 

  104. 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 509:381–384. https://doi.org/10.1038/nature13117.Structure

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Barth H, Schäfer C, Adah MI, Zhang F, Linhardt RJ, Toyoda H, Kinoshita-Toyoda A, Toida T, van Kuppevelt TH, Depla E, von Weizsäcker F, Blum HE, Baumert TF (2003) Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate. J Biol Chem 278:41003–41012. https://doi.org/10.1074/jbc.M302267200

    Article  PubMed  Google Scholar 

  106. Shi Q, Jiang J, Luo G (2013) Syndecan-1 serves as the major receptor for attachment of hepatitis C virus to the surfaces of hepatocytes. J Virol 87:6866–6875. https://doi.org/10.1128/JVI.03475-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lefevre M, Felmlee DJ, Parnot M, Baumert TF, Schuster C (2014) Syndecan 4 is involved in mediating HCV entry through interaction with lipoviral particle-associated apolipoprotein E. PLoS One 9:3–10. https://doi.org/10.1371/journal.pone.0095550

    Article  Google Scholar 

  108. 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 282:938–942 (80-.)

    Article  CAS  PubMed  Google Scholar 

  109. Owen DM, Huang H, Ye J, Gale M Jr (2010) Apolipoprotein E on hepatitis C virion facilitates infection through interaction with low density lipoprotein receptor. Virology 394:99–108. https://doi.org/10.1016/j.virol.2009.08.037

    Article  CAS  Google Scholar 

  110. Zeisel MB, Koutsoudakis G, Schnober EK, Haberstroh A, Blum HE, Cosset F-L, Wakita T, Jaeck D, Doffoel M, Royer C, Soulier E, Schvoerer E, Schuster C, Stoll-Keller F, Bartenschlager R, Pietschmann T, Barth H, Baumert TF (2007) Scavenger receptor class B Type I is a key host factor for hepatitis C virus infection required for an entry step closely linked to CD81. Hepatology 46:1–3. https://doi.org/10.1002/hep.21994

    Article  CAS  Google Scholar 

  111. Lupberger J, Zeisel MB, Xiao F, Thumann C, Fofana I, Zona L, Davis C, Mee CJ, Turek M, Gorke S, Royer C, Fischer B, Zahid MN, Lavillette D, Fresquet J, Cosset F-L, Rothenberg SM, Pietschmann T, Patel AH, Pessaux P, Doffoël M, Raffelsberger W, Poch O, McKeating JA, Brino L, Baumert TF (2011) EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat Med 17:589–595. https://doi.org/10.1038/nm.2341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Farquhar MJ, Hu K, Harris HJ, Davis C, Brimacombe CL, Fletcher SJ, Baumert TF, Rappoport JZ, Balfe P, McKeating JA (2012) Hepatitis C virus induces CD81 and Claudin-1 endocytosis. J Virol 86:4305–4316. https://doi.org/10.1128/JVI.06996-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Dubuisson J, Cosset F-L (2014) Virology and cell biology of the hepatitis C virus life cycle—An update. J Hepatol 61:S3–S13. https://doi.org/10.1016/j.jhep.2014.06.031

    Article  CAS  PubMed  Google Scholar 

  114. Verrier ER, Colpitts CC, Bach C, Heydmann L, Zona L, Xiao F, Thumann C, Crouchet E, Gaudin R, Sureau C, Cosset F-L, McKeating JA, Pessaux P, Hoshida Y, Schuster C, Zeisel MB, Baumert TF (2016) Solute carrier NTCP regulates innate antiviral immune responses targeting hepatitis C virus infection of hepatocytes. Cell Rep 17:1357–1368. https://doi.org/10.1016/j.celrep.2016.09.084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Smith SE, Weston S, Kellam P, Marsh M (2014) IFITM proteins—cellular inhibitors of viral entry. Curr Opin Virol 4:71–77. https://doi.org/10.1016/j.coviro.2013.11.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wilkins C, Woodward J, Lau DT-Y, Barnes A, Joyce M, McFarlane N, McKeating J, Tyrrell DL, Gale M Jr (2013) IFITM1 is a tight junction protein that inhibits hepatitis C virus entry. Hepatology 57:461–469. https://doi.org/10.1002/hep.26066.IFITM1

    Article  CAS  PubMed  Google Scholar 

  117. Narayana SK, Helbig KJ, Mccartney EM, Eyre NS, Bull RA, Eltahla A, Lloyd AR, Beard MR (2015) The interferon-induced transmembrane proteins, IFITM1, IFITM2, and IFITM3 inhibit hepatitis C virus entry. J Biol Chem 290:25946–25959. https://doi.org/10.1074/jbc.M115.657346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chang K-O, George DW (2007) Bile acids promote the expression of hepatitis C virus in replicon-harboring cells. J Virol 81:9633–9640. https://doi.org/10.1128/JVI.00795-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by Inserm, the University of Strasbourg, the European Union (ERC-2014-AdG-671231-HEPCIR, Infect-ERA hepBccc, EU H2020 Hep-CAR 667273), ANRS (2015/1099), the French Cancer Agency (ARC IHU201301187) and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R03AI131066. CCC acknowledges fellowships from the Canadian Institutes of Health Research (201411MFE-338606-245517) and the Canadian Network on Hepatitis C. ERV is the recipient of an ANRS fellowship (ECTZ50121).

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Authors and Affiliations

  1. Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 3 Rue Koeberlé, 67000, Strasbourg, France

    Carla Eller, Laura Heydmann, Eloi R. Verrier, Catherine Schuster & Thomas F. Baumert

  2. Université de Strasbourg, 67000, Strasbourg, France

    Carla Eller, Laura Heydmann, Eloi R. Verrier, Catherine Schuster & Thomas F. Baumert

  3. Division of Infection and Immunity, University College London, London, UK

    Che C. Colpitts

  4. Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000, Strasbourg, France

    Thomas F. Baumert

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  1. Carla Eller
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  4. Eloi R. Verrier
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CFE, LH, CCC, ERV, CS, TFB wrote the manuscript.

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Correspondence to Thomas F. Baumert.

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Eller, C., Heydmann, L., Colpitts, C.C. et al. The functional role of sodium taurocholate cotransporting polypeptide NTCP in the life cycle of hepatitis B, C and D viruses. Cell. Mol. Life Sci. 75, 3895–3905 (2018). https://doi.org/10.1007/s00018-018-2892-y

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