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キネシン-輸送基質相互作用特異性の解明と新規ウイルス感染阻害アプローチ

Research Project

Project/Area Number 23K06575
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 49060:Virology-related
Research InstitutionNational Institute of Infectious Diseases

Principal Investigator

アリ フセインハッサン  国立感染症研究所, ウイルス第二部, 主任研究官 (00523515)

Project Period (FY) 2023-04-01 – 2026-03-31
Project Status Granted (Fiscal Year 2023)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2025: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2024: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
KeywordsKinesins / Specificity / Substrate / Hepatitis / NTCP / KIF4A / Viral entry
Outline of Research at the Start

KIF4A mediates the transport of NTCP, ITGB1, and L1CAM to the cell surface. Hence, we hypothesized that these proteins must share certain structural similarities through which they can be recognized and transported to the cell surface by KIF4A. Our seed data showed that C-terminal transmembrane domain of NTCP is required to interact with KIF4A. This region is also present in 2 other proteins reported to be transported by KIF4A (ITGB1 and L1CAM). In 2023 we will confirm the role of the C-terminal leucine rich region on KIF4A-mediated transport of ITGB1 and L1CAM to the cell surface.

Outline of Annual Research Achievements

We previously identified a poly Lysine motif at the C-terminal part of NTCP to be the binding site for KIF4A. In 2023, we further performed substitution mutation, and identified 2 amino acids to be essential for this interaction by co-immunoprecipitation assays. KIF4 is reported to bind with ITGB1 and transport it to cell surface. We identified a similar poly-lysine motif in ITGB1; we performed substitution mutation of the similar amino acids that were important for the interaction between KIF4A and NTCP; and found that it suppressed the interaction of ITGB1 with KIF4 by immunoprecipitation assays. These data confirmed the sequence in KIF4 substrates that is required for its identification, interaction, and transport by KIF4.

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

As planed in the research proposal, in 2023 we identified the amino acids required for the interaction of KIF4A with its substrates. We confirmed the importance of these amino acids in 2 different KIF4A substrates and proved that substitution of these amino acids reduced the surface transport of these proteins.

Strategy for Future Research Activity

We previously showed that the interaction of KIF4A and its substrate is indirect. As planed in the submitted project, in FY2024 we are planning to identify the adaptor protein/s which are required for this interaction. Using the wild type C-terminal sequence of NTCP and ITCB1 together with the mutant sequence carrying substitution in only the 2 important amino acids identified in 2023, we will perform co-immunoprecipitation assay, followed by mass spectrometry to identify the adaptor protein which will bind to WT but not mutant sequence. We will then analyze the effect of this protein on KIF4A/NTCP interaction.

Report

(1 results)
  • 2023 Research-status Report
  • Research Products

    (3 results)

All 2024 2023

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (2 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Antiviral effect of peptoids on hepatitis B virus infection in cell culture2024

    • Author(s)
      Murayama Asako、Igarashi Hitomi、Yamada Norie、Aly Hussein Hassan、Molchanova Natalia、Lin Jennifer S.、Nishitsuji Hironori、Shimotohno Kunitada、Muramatsu Masamichi、Barron Annelise E.、Kato Takanobu
    • Journal Title

      Antiviral Research

      Volume: 223 Pages: 105821-105821

    • DOI

      10.1016/j.antiviral.2024.105821

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] A newly developed RXR agonist inhibits HBV/HDV internalization in vitro through blocking KIF4-mediated NTCP surface trafficking2023

    • Author(s)
      3.Sameh A. Gad, Daniel Merk, Takanobu Kato, Masamichi Muramatsu, Kazuaki Chayama, Takaji Wakita, Hussein H. Aly
    • Organizer
      70th Annual Meeting of the Japanese Society for Virology
    • Related Report
      2023 Research-status Report
  • [Presentation] A newly developed RXR agonist blocked KIF4 mediated NTCP surface trafficking and NTCP dependent HBV/HDV internalization in vitro.2023

    • Author(s)
      5.Sameh A. Gad, Daniel Merk, Takanobu Kato, Masamichi Muramatsu, Kazuaki Chayama, Takaji Wakita, Hussein H. Aly.
    • Organizer
      the 37th annual International HBV Meeting 2023
    • Related Report
      2023 Research-status Report
    • Int'l Joint Research

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Published: 2023-04-13   Modified: 2024-12-25  

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