Mechanistic analysis of hepatitis B virus internalization focusing on NTCP oligomerization
Project/Area Number |
19K23855
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Research Category |
Grant-in-Aid for Research Activity Start-up
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Allocation Type | Multi-year Fund |
Review Section |
0803:Pathology, infection/immunology, and related fields
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Research Institution | National 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)
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Project Period (FY) |
2019-08-30 – 2022-03-31
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Project Status |
Completed (Fiscal Year 2021)
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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)
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Keywords | B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。
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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.
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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。
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Report
(4 results)
Research Products
(26 results)
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[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.
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Journal Title
Cancer Med
Volume: 20
Issue: 20
Pages: 7663-7671
DOI
Related Report
Peer Reviewed / Open Access
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[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
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Journal Title
Scientific Reports
Volume: 10
Issue: 1
Pages: 20763-20763
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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
Int'l Joint Research
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[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
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[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
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[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
Int'l Joint Research
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