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Mechanistic analysis of hepatitis B virus internalization focusing on NTCP oligomerization

Research Project

Project/Area Number 19K23855
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0803:Pathology, infection/immunology, and related fields
Research InstitutionNational Center for Global Health and Medicine (2021)
National Institute of Infectious Diseases (2019-2020)

Principal Investigator

Fukano Kento  国立研究開発法人国立国際医療研究センター, 臨床研究センター, 産学連携推進部 上級研究員 (80848531)

Project Period (FY) 2019-08-30 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsB型肝炎ウイルス / 内在化 / NTCP / 多量体 / HBV / EGFR / 侵入 / 感染 / 多量体化
Outline of Research at the Start

B型肝炎ウイルス(HBV)は感染受容体であるNTCPに吸着後、細胞内へ侵入すると報告されている。しかし、HBVが細胞内に侵入する内在化のメカニズムに関しては未だほとんど解明されていない。これまでにそのHBV内在化にNTCPの多量体形成が関与することを示したため、本研究ではこれまでの結果を踏まえ、HBV内在化におけるNTCP多量体化の必要性を解析し、HBVの感染機構を明らかにする。また、それを標的とした創薬シーズの開発という応用まで見据えた研究を行う。

Outline of Final Research Achievements

Elucidation of molecular mechanism for hepatitis B virus (HBV) infection is required for developing of new prevention and treatment against HBV-related liver diseases. Recently, we reported that oligomerization of bile acid transporter (NTCP), which is an HBV entry receptor, plays a critical role in the HBV internalization pathway. In this study, we identified an amino acid essential for NTCP oligomerization by alanine scanning mutagenesis. Additionally, we revealed that NTCP oligomerization is initiated downstream of the NTCP-EGFR interaction and then triggers HBV internalization. This study provides significant insight into the HBV entry mechanisms.

Academic Significance and Societal Importance of the Research Achievements

HBVの細胞内への内在化機構において、NTCPの多量体形成やEGFRとの相互作用が重要であるとこれまで明らかになっているが、その2つの機構の関連性は不明であった。本研究により、NTCP-EGFR相互作用の下流でNTCPの多量体化が起こると明らかになり、HBV感染機構の一端を解明したと同時に、NTCP多量体化およびHBV内在化の過程が新たな創薬標的となり得ることを示した。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (26 results)

All 2022 2021 2020 2019

All Journal Article (7 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 7 results,  Open Access: 4 results) Presentation (19 results) (of which Int'l Joint Research: 7 results)

  • [Journal Article] The kinesin KIF4 mediates HBV/HDV entry through the regulation of surface NTCP localization and can be targeted by RXR agonists in vitro2022

    • Author(s)
      Gad Sameh A.、Sugiyama Masaya、Tsuge Masataka、Wakae Kosho、Fukano Kento、Oshima Mizuki、Sureau Camille、Watanabe Noriyuki、Kato Takanobu、Murayama Asako、Li Yingfang、Shoji Ikuo、Shimotohno Kunitada、Chayama Kazuaki、Muramatsu Masamichi、Wakita Takaji、Nozaki Tomoyoshi、Aly Hussein H.
    • Journal Title

      PLOS Pathogens

      Volume: 18 Issue: 3 Pages: 1-26

    • DOI

      10.1371/journal.ppat.1009983

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification of natural compounds extracted from crude drugs as novel inhibitors of hepatitis C virus2021

    • Author(s)
      Zheng Xin、Guo Rui、Liu Qingbo、Wakae Kousho、Watanabe Noriyuki、Fukano Kento、Que Lusheng、Li Yingfang、Aly Hussein H.、Watashi Koichi、Suzuki Ryosuke、Murayama Asako、Kato Takanobu、Aizaki Hideki、Wakita Takaji、Huang Xiaoxiao、Yan Yi、Song Shao-Jiang、Muramatsu Masamichi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 567 Pages: 1-8

    • DOI

      10.1016/j.bbrc.2021.06.022

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] NTCP Oligomerization Occurs Downstream of the NTCP-EGFR Interaction during Hepatitis B Virus Internalization2021

    • Author(s)
      Fukano Kento、Oshima Mizuki、Tsukuda Senko、Aizaki Hideki、Ohki Mio、Park Sam-Yong、Wakita Takaji、Wakae Kousho、Watashi Koichi、Muramatsu Masamichi
    • Journal Title

      Journal of Virology

      Volume: 95 Issue: 24 Pages: 1-12

    • DOI

      10.1128/jvi.00938-21

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] EBV-LMP1 induces APOBEC3s and mitochondrial DNA hypermutation in nasopharyngeal cancer2020

    • Author(s)
      Wakae K, Kondo S, Pham HT, Wakisaka N, Que L, Li Y, Zheng X, Fukano K, Kitamura K, Watashi K, Aizaki H, Ueno T, Moriyama-Kita M, Ishikawa K, Nakanishi Y, Endo K, Muramatsu M, Yoshizaki T.
    • Journal Title

      Cancer Med

      Volume: 20 Issue: 20 Pages: 7663-7671

    • DOI

      10.1002/cam4.3357

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] MCPIP1 reduces HBV-RNA by targeting its epsilon structure2020

    • Author(s)
      Li Yingfang、Que Lusheng、Fukano Kento、Koura Miki、Kitamura Kouichi、Zheng Xin、Kato Takanobu、Aly Hussein Hassan、Watashi Koichi、Tsukuda Senko、Aizaki Hideki、Watanabe Noriyuki、Sato Yuko、Suzuki Tadaki、Suzuki Hiroshi I.、Hosomichi Kazuyoshi、Kurachi Makoto、Wakae Kousho、Muramatsu Masamichi
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 20763-20763

    • DOI

      10.1038/s41598-020-77166-z

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] B型肝炎ウイルスの感染機序と創薬2020

    • Author(s)
      深野 顕人、渡士 幸一
    • Journal Title

      Farumashia

      Volume: 56 Issue: 12 Pages: 1079-1083

    • DOI

      10.14894/faruawpsj.56.12_1079

    • NAID

      130007948621

    • ISSN
      0014-8601, 2189-7026
    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Non-nucleoside hepatitis B virus polymerase inhibitors identified by an in vitro polymerase elongation assay2019

    • Author(s)
      Nakajima Shogo、Watashi Koichi、Fukano Kento、Tsukuda Senko、Wakae Kousho、Aizaki Hideki、Muramatsu Masamichi、Wakita Takaji、Toyoda Tetsuya
    • Journal Title

      Journal of Gastroenterology

      Volume: 55 Issue: 4 Pages: 441-452

    • DOI

      10.1007/s00535-019-01643-0

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] 新規作用機序によりB型肝炎ウイルス感染を阻害する酸化ステロール合成誘導体の同定2022

    • Author(s)
      大嶋美月、深野顕人、岩本将士、Frank Stappenbeck、Feng Wang、鄭シン、山崎雅子、若江亨祥、相崎英樹、倉持幸司、村松正道、脇田隆字、Farhad Parhami、渡士幸一
    • Organizer
      日本薬学会第142年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 感染受容体NTCPの多量体化が導くB型肝炎ウイルス細胞内侵入機構の解明2022

    • Author(s)
      深野顕人、九十田千子、大嶋美月、大木規央、朴三用、若江亨祥、相崎英樹、脇田隆字、渡士幸一、村松正道
    • Organizer
      日本薬学会第142年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] A biflavonoid amentoflavone inhibits hepatitis B virus infection2021

    • Author(s)
      Aoki-Utsubo C, Indrasetiawan P, Fukano K, Muramatsu M, Hotta H, Kameoka M
    • Organizer
      The 11th JSP・CSP・KSP Joint Symposium on Pharmacognosy
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] MCPIP1 reduces HBV-RNA by targeting its epsilon structure2021

    • Author(s)
      Li Y, Que L, Fukano K, Koura M, Kitamura K, Wakae K, Muramatsu M
    • Organizer
      2021 International HBV Meeting
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Kinesin KIF4 is a key regulator for surface localization of NTCP, and HBV/HDV infection2021

    • Author(s)
      Gad SA, Sugiyama M, Tsuge M, Wakae K, Fukano K, Watanabe N, Kato T, Murayama A, Li Y, Shoji I, Shimotohno K, Chayama K, Muramatsu M, Wakita T, Nozaki T, Aly HH
    • Organizer
      2021 International HBV Meeting
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] SLC10A1/NTCP多量体形成が制御するB型肝炎ウイルス細胞内侵入機構の解析2021

    • Author(s)
      深野顕人、大嶋美月、九十田千子、相崎英樹、大木規央、朴三用、脇田隆字、若江亨祥、渡士幸一、村松正道
    • Organizer
      第94回日本生化学会大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] アメントフラボンのB型肝炎ウイルス感染阻害活性について2021

    • Author(s)
      靱千恵、Puguh Indrasetiawan、深野顕人、村松正道、堀田博、亀岡正典
    • Organizer
      第68回日本ウイルス学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] B型肝炎ウイルスpreS2領域に対する抗体はウイルス感染を抑制する2021

    • Author(s)
      矢藤慶悟、深野顕人、松田麻未、田中智久、森石恆司、西辻裕紀、下遠野邦忠、田村浩二、加藤孝宣、村松正道、鈴木 亮介
    • Organizer
      第68回日本ウイルス学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] NTCP oligomerization is initiated downstream of the NTCP-EGFR interaction during HBV internalization2021

    • Author(s)
      Fukano K, Oshima M, Tsukuda S, Aizaki H, Ohki M, Park SY, Wakita T, Wakae K, Watashi K, Muramatsu M
    • Organizer
      2021 International HBV Meeting
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Identification of an oxysterol derivative that inhibits HBV infection by interrupting NTCP oligomerization2021

    • Author(s)
      Oshima M, Fukano K, Iwamoto M, Stappenbeck F, Wang F, Zheng X, Yamasaki M, Wakae K, Aizaki H, Kuramochi K, Muramatsu M, Wakita T, Parhami F, Watashi K
    • Organizer
      第68回日本ウイルス学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] The kinesin KIF4 is essential to promote HBV/HDV entry through the regulation of surface localization of NTCP, and is a possible target for anti-HBV/HDV therapy2021

    • Author(s)
      Gad SA, Wakae K, Fukano K, Kato T, Shoji I, Shimotohno K, Chayama K, Muramatsu M, Wakita T, Nozaki T, Aly HH
    • Organizer
      第68回日本ウイルス学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Functional relevance between NTCP oligomerization and EGFR during hepatitis B virus internalization2021

    • Author(s)
      Fukano K, Oshima M, Tsukuda S, Aizaki H, Ohki M, Park SY, Wakita T, Wakae K, Watashi K, Muramatsu M
    • Organizer
      第68回日本ウイルス学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Identification of a novel inhibitor for hepatitis B virus internalization targeting viral receptor oligomerization2020

    • Author(s)
      Fukano K, Tsukuda S, Oshima M, Ohki M, Park SY, Wakae K, Aizaki H, Wakita T, Watashi K, Muramatsu M
    • Organizer
      Virtual PSWC2020
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] MCPIP1はエプシロン構造を介してB型肝炎ウイルスRNAを分解する2020

    • Author(s)
      李瑩芳、闕路晟、深野顕人、小浦美樹、喜多村晃一、倉知慎、若江亨祥、村松正道
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Research-status Report
  • [Presentation] B型肝炎ウイルス内在化機構における感染受容体多量体化の関与2020

    • Author(s)
      深野顕人、九十田千子、大嶋美月、大木規央、朴三用、若江亨祥、相崎英樹、脇田隆字、渡士幸一、村松正道
    • Organizer
      日本薬学会第140年会
    • Related Report
      2019 Research-status Report
  • [Presentation] Interference with NTCP oligomerization impairs the HBV internalization2019

    • Author(s)
      Fukano K, Tsukuda S, Oshima M, Suzuki R, Aizaki H, Ohki M, Park SY, Muramatsu M, Wakita T, Sureau C, Ogasawara Y, Watashi K
    • Organizer
      7th JAPAN-TAIWAN-KOREA HBV Research Symposium 2019
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 酸化コレステロールによるHBV内在化阻害とその機構の解析2019

    • Author(s)
      大嶋美月、深野顕人、岩本将士、若江亨祥、相崎英樹、村松正道、脇田隆字、渡士幸一
    • Organizer
      第16回ウイルス学キャンプin湯河原
    • Related Report
      2019 Research-status Report
  • [Presentation] NTCP oligomerization involved in hepatitis B virus internalization2019

    • Author(s)
      Fukano K, Tsukuda S, Oshima M, Ohki M, Park SY, Wakae K, Aizaki H, Wakita T, Muramatsu M, Watashi K
    • Organizer
      2019 International HBV Meeting
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] NTCP多量体化によるB型肝炎ウイルス内在化制御機構2019

    • Author(s)
      深野顕人、九十田千子、大嶋美月、大木規央、朴三用、若江亨祥、相崎英樹、脇田隆字、村松正道、渡士幸一
    • Organizer
      第67回日本ウイルス学会学術集会
    • Related Report
      2019 Research-status Report

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Published: 2019-09-03   Modified: 2023-01-30  

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