Epidermal growth factor receptor is a host-entry cofactor triggering hepatitis B virus internalization

Masashi Iwamoto, Wakana Saso, Ryuichi Sugiyama, Koji Ishii, Mio Ohki, Shushi Nagamori, Ryosuke Suzuki, Hideki Aizaki, Akihide Ryo, Ji Hye Yun, Sam Yong Park, Naoko Ohtani, Masamichi Muramatsu, Shingo Iwami, Yasuhito Tanaka, Camille Sureau, Takaji Wakita, Koichi Watashi

Research output: Contribution to journalArticlepeer-review

137 Citations (Scopus)


Sodium taurocholate cotransporting polypeptide (NTCP) is a host cell receptor required for hepatitis B virus (HBV) entry. However, the susceptibility of NTCP-expressing cells to HBV is diverse depending on the culture condition. Stimulation with epidermal growth factor (EGF) was found to potentiate cell susceptibility to HBV infection. Here, we show that EGF receptor (EGFR) plays a critical role in HBV virion internalization. In EGFR-knockdown cells, HBV or its preS1-specific fluorescence peptide attached to the cell surface, but its internalization was attenuated. PreS1 internalization and HBV infection could be rescued by complementation with functional EGFR. Interestingly, the HBV/preS1–NTCP complex at the cell surface was internalized concomitant with the endocytotic relocalization of EGFR. Molecular interaction between NTCP and EGFR was documented by immunoprecipitation assay. Upon dissociation from functional EGFR, NTCP no longer functioned to support viral infection, as demonstrated by either (i) the introduction of NTCP point mutation that disrupted its interaction with EGFR, (ii) the detrimental effect of decoy peptide interrupting the NTCP–EGFR interaction, or (iii) the pharmacological inactivation of EGFR. Together, these data support the crucial role of EGFR in mediating HBV–NTCP internalization into susceptible cells. EGFR thus provides a yet unidentified missing link from the cell-surface HBV–NTCP attachment to the viral invasion beyond the host cell membrane.

Original languageEnglish
Pages (from-to)8487-8492
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
Publication statusPublished - 2019

All Science Journal Classification (ASJC) codes

  • General


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