The machinery for endocytosis of epidermal growth factor receptor coordinates the transport of incoming hepatitis B virus to the endosomal network

Masashi Iwamoto, Wakana Saso, Kazane Nishioka, Hirofumi Ohashi, Ryuichi Sugiyama, Akihide Ryo, Mio Ohki, Ji Hye Yun, Sam Yong Park, Takayuki Ohshima, Ryosuke Suzuki, Hideki Aizaki, Masamichi Muramatsu, Tetsuro Matano, Shingo Iwami, Camille Sureau, Takaji Wakita, Koichi Watashi

Research output: Contribution to journalArticle

Abstract

Sodium taurocholate cotransporting polypeptide (NTCP) is expressed at the surface of human hepatocytes and functions as an entry receptor of hepatitis B virus (HBV). Recently, we have reported that epidermal growth factor receptor (EGFR) is involved in NTCP-mediated viral internalization during the cell entry process. Here, we analyzed which function of EGFR is essential for mediating HBV internalization. In contrast to the reported crucial function of EGFR-downstream signaling for the entry of hepatitis C virus (HCV), blockade of EGFR-downstream signaling proteins, including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), and signal transducer and activator of transcription (STAT), had no or only minor effects on HBV infection. Instead, deficiency of EGFR endocytosis resulting from either a deleterious mutation in EGFR or genetic knockdown of endocytosis adaptor molecules abrogated internalization of HBV via NTCP and prevented viral infection. EGFR activation triggered a time-dependent relocalization of HBV preS1 to the early and late endosomes and to lysosomes in concert with EGFR transport. Suppression of EGFR ubiquitination by site-directed mutagenesis or by knocking down two EGFR-sorting molecules, signal-transducing adaptor molecule (STAM) and lysosomal protein transmembrane 4β (LAPTM4B), suggested thatEGFRtransport to the late endosome is critical for efficient HBV infection. Cumulatively, these results support the idea that theEGFRendocytosis/sorting machinery drives the translocation of NTCP-bound HBV from the cell surface to the endosomal network, which eventually enables productive viral infection.

Original languageEnglish
Pages (from-to)800-807
Number of pages8
JournalJournal of Biological Chemistry
Volume295
Issue number3
DOIs
Publication statusPublished - Jan 17 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Iwamoto, M., Saso, W., Nishioka, K., Ohashi, H., Sugiyama, R., Ryo, A., Ohki, M., Yun, J. H., Park, S. Y., Ohshima, T., Suzuki, R., Aizaki, H., Muramatsu, M., Matano, T., Iwami, S., Sureau, C., Wakita, T., & Watashi, K. (2020). The machinery for endocytosis of epidermal growth factor receptor coordinates the transport of incoming hepatitis B virus to the endosomal network. Journal of Biological Chemistry, 295(3), 800-807. https://doi.org/10.1074/jbc.AC119.010366