CD46 regulates hepatitis B virus entry by modulating cell-surface NTCP levels through cis-interaction

Kei Miyakawa; Yusuke Nakai; Taichi Kameya; Hironori Nishitsuji; Koichi Watashi; Makoto Takeda; Tsukasa Seya; Kunitada Shimotohno; Yayoi Kimura; Akihide Ryo

doi:10.1093/jmcb/mjaf055

CD46 regulates hepatitis B virus entry by modulating cell-surface NTCP levels through cis-interaction

J Mol Cell Biol. 2025 Dec 23:mjaf055. doi: 10.1093/jmcb/mjaf055. Online ahead of print.

Authors

Kei Miyakawa^{1

2

3

4}, Yusuke Nakai², Taichi Kameya^{5

6}, Hironori Nishitsuji⁷, Koichi Watashi⁸, Makoto Takeda⁹, Tsukasa Seya¹⁰, Kunitada Shimotohno¹¹, Yayoi Kimura¹², Akihide Ryo^{4

5}

Affiliations

¹ AIDS Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security, Tokyo 208-0011, Japan.
² Influenza Research Center, National Institute of Infectious Diseases, Japan Institute for Health Security, Tokyo 208-0011, Japan.
³ Institute for Vaccine Research and Development, Hokkaido University, Hokkaido, Japan.
⁴ Department of Microbiology, Yokohama City University School of Medicine, Kanagawa, Japan.
⁵ Department of Bioinformatics and Integrative Omics, National Institute of Infectious Diseases, Japan Institute for Health Security, Tokyo 208-0011, Japan.
⁶ Life Science Laboratory, Technology and Development Division, Kanto Chemical Co., Inc., Kanagawa, Japan.
⁷ Department of Virology, Fujita Health University School of Medicine, Aichi, Japan.
⁸ Department of Drug Development, National Institute of Infectious Diseases, Japan Institute for Health Security, Tokyo 208-0011, Japan.
⁹ Department of Microbiology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
¹⁰ Nebuta Research Institute for Life Sciences, Aomori University, Aomori, Japan.
¹¹ Institute of Microbial Chemistry (BIKAKEN), Tokyo, Japan.
¹² Advanced Medical Research Center, Yokohama City University, Kanagawa, Japan.

PMID: 41432296
DOI: 10.1093/jmcb/mjaf055

Abstract

Hepatitis B virus (HBV) infection remains a major global health challenge. While sodium taurocholate co-transporting polypeptide (NTCP) is the primary receptor for HBV entry, the molecular mechanisms regulating NTCP-mediated viral entry remain incompletely understood. Here, we identified CD46 as a crucial regulatory factor for NTCP membrane expression. We found that CD46 interacted with NTCP in cis at the plasma membrane through proximity-based labeling screening. The depletion of CD46 significantly reduced cell-surface NTCP levels and HBV infection in hepatocytes. Anti-CD46 monoclonal antibodies, particularly clone E4.3, inhibited HBV infection by triggering NTCP internalization from the plasma membrane to intracellular vesicles. The antiviral effect of CD46 antibodies was also confirmed in primary human hepatocytes. Our study reveals a previously unknown mechanism regulating NTCP-mediated HBV entry and suggests CD46 as a potential therapeutic target for HBV infection.

Keywords: hepatitis B virus (HBV); proximity-based labeling; sodium taurocholate co-transporting polypeptide (NTCP); viral entry.