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

TLDR

Human hepatitis B virus causes significant disease worldwide, and co‑infection with hepatitis D virus worsens outcomes; viral entry depends on envelope proteins, particularly the pre‑S1 domain, but the cellular receptor mediating this interaction has remained unidentified. Using near‑zero‑distance photo‑cross‑linking and tandem affinity purification, the authors identified the pre‑S1 receptor‑binding region as specifically interacting with the liver‑expressed transporter sodium taurocholate cotransporting polypeptide (NTCP). Silencing NTCP blocked HBV and HDV infection, while ectopic expression or humanization of monkey NTCP restored susceptibility, confirming NTCP as a functional receptor for both viruses.

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.