Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

Elife. 2012 Nov 13:3. doi: 10.7554/eLife.00049.

Abstract

Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157-165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV.

Keywords: Sodium taurocholate cotransporting polypeptide; biochemistry; hepatitis B virus; hepatitis D virus; infectious disease; liver; microbiology; receptor; virus infection; viruses.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Cells, Cultured
  • Disease Susceptibility
  • Hepatitis B / pathology
  • Hepatitis B / virology
  • Hepatitis B virus / metabolism*
  • Hepatitis D / pathology
  • Hepatitis D / virology
  • Hepatitis Delta Virus / metabolism*
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Hepatocytes / virology
  • Humans
  • Ligands
  • Molecular Sequence Data
  • Organic Anion Transporters, Sodium-Dependent / chemistry
  • Organic Anion Transporters, Sodium-Dependent / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Virus / chemistry
  • Receptors, Virus / metabolism*
  • Reproducibility of Results
  • Symporters / chemistry
  • Symporters / metabolism*
  • Tupaiidae
  • Virion / metabolism

Substances

  • Ligands
  • Organic Anion Transporters, Sodium-Dependent
  • Receptors, Virus
  • Symporters
  • sodium-bile acid cotransporter