In silico search and functional analysis for genes having differentially localized protein isoforms via alternative splicing and alternative translation initiation

• Project/Area Number: 18K11543
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 62010:Life, health and medical informatics-related
• Research Institution: National Institute of Advanced Industrial Science and Technology
• Principal Investigator: Kenichiro Imai 国立研究開発法人産業技術総合研究所, 生命工学領域, 主任研究員 (80442573)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: アイソフォーム / 細胞内局在 / ターゲッティングシグナル予測 / 多機能性 / 選択的スプライシング / 選択的翻訳開始点 / 細胞内局在部位変化 / 多機能性タンパク質 / 細胞内局在変化 / 局在化シグナル

Outline of Final Research Achievements

In humans, most genes produce multiple isoforms via alternative splicing or alternative translation initiation. Several cases are known in which isoforms of the same gene exhibit change of localization to regulate cellular function. However, the precise number of genes having differentially localized protein isoforms produced from the human genome is still unknown. Thus, we explored genes having differentially localized protein isoforms based on prediction of gain or loss of N-terminal targeting signals; mitochondrial targeting signal (MTS) and ER signal peptide (SP). We found about 60% of predicted genes containing MTS are possibility to change localization sites at isoform level (741 genes) while about 30% might change localization sites in predicted genes containing SP (1055 gene). Furthermore, we found more than a dozen of promising candidates of differentially localized protein isoforms by analysis of structure, function, and transcript expression of the protein isoforms.

Academic Significance and Societal Importance of the Research Achievements

遺伝子の重要な機能調節として、選択的スプライシングや選択的翻訳開始点によりN末端のターゲッティングシグナルの欠損/獲得による細胞内局在の変化とそれに伴う機能調節があるが、いったいどれほどの遺伝子が、どのような条件によって、このような細胞機能の調節を行うかは未だよくわかっていない。これに対し、本研究では、MTSの欠失/獲得よりアイソフォームレベルで局在変化を起こし、新たな機能調節を行う遺伝子候補を見出すことができた。今後、実験的検証を進めていくが、本研究で得られた成果は、アイソフォームレベルでの局在変化による機能調節機序の解明への重要なリソースとなると考えられる。

Research Products

• [Journal Article] Role of the TOM complex in Protein Import into Mitochondria: Structural Views (2022)
  • Author(s): Araiso Y, Imai K, Endo T
  • Journal Title: Annu Rev Biochem Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Unfolding is the driving force for mitochondrial import and degradation of the Parkinson's disease-related protein DJ-1 (2021)
  • Author(s): Queliconi BB, Kojima W, Kimura M, Imai K, Udagawa C, Motono C, Hirokawa T, Tashiro S, Caaveiro JMM, Tsumoto K, Yamano K, Tanaka K, Matsuda N
  • Journal Title: J Cell Sci Volume: 134 Issue: 22 Pages: 1-1
  • DOI: 10.1242/jcs.258653
  • Peer Reviewed / Open Access
• [Journal Article] Distinct mutations in importin-β family nucleocytoplasmic transport receptors transportin-SR and importin-13 affect specific cargo binding (2021)
  • Author(s): Kimura M, Imai K, Morinaka Y, Hosono-Sakuma Y, Horton P, Imamoto N
  • Journal Title: Sci Rep. Volume: 11 Issue: 1 Pages: 15649-15649
  • DOI: 10.1038/s41598-021-94948-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural snapshot of the mitochondrial protein import gate (2021)
  • Author(s): Araiso Y, Imai K, Endo T
  • Journal Title: FEBS J Volume: - Issue: 18 Pages: 1-11
  • DOI: 10.1111/febs.15661
  • Peer Reviewed / Open Access
• [Journal Article] Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy (2021)
  • Author(s): Kojima W, Yamano K, Kosako H, Imai K, Kikuchi R, Tanaka K, Matsuda N
  • Journal Title: Autophagy Volume: - Issue: 8 Pages: 1-26
  • DOI: 10.1080/15548627.2021.1874133
  • NAID: 120007174412
  • Peer Reviewed / Open Access
• [Journal Article] Mitochondrial sorting and assembly machinery operates by β-barrel switching (2021)
  • Author(s): Takeda H, Tsutsumi A, Nishizawa T, Lindau C, Busto JV, Wenz LS, Ellenrieder L, Imai K, Straub SP, Mossmann W, Qiu J, Yamamori Y, Tomii K, Suzuki J, Murata T, Ogasawara S, Nureki O, Becker T, Pfanner N, Wiedemann N, Kikkawa M, Endo T.
  • Journal Title: Nature Volume: 590(7844) Issue: 7844 Pages: 163-169
  • DOI: 10.1038/s41586-020-03113-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Subcellular Localization of Proteins From Their Amino Acid Sequences (2020)
  • Author(s): Imai K, Nakai K
  • Journal Title: Front Genet. Volume: 11 Pages: 607812-607812
  • DOI: 10.3389/fgene.2020.607812
  • Peer Reviewed / Open Access
• [Journal Article] Structure of mitochondrial import gate reveals distinct preprotein paths. (2019)
  • Author(s): Araiso, Y., Tsutsumi, A., Qui, J., Imai, K., Shiota, T., Song, J., Lindau, C., Wenz, LS., Sakaue,H., Yunoki, K., Kawano, S., Suzuki, J., Wichnewski, M., Schutze, C., Ariyama, H., Ando, T., Becker, T., Lithgow, T., Weidemann, N., Pfanner, N., Kikkawa, M., Endo, T.
  • Journal Title: Nature Volume: 575 Issue: 7782 Pages: 395-401
  • DOI: 10.1038/s41586-019-1680-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An Entamoeba-Specific Mitosomal Membrane Protein with Potential Association to the Golgi Apparatus. (2019)
  • Author(s): Santos, H.J., Hanadate, Y., Imai, K., Nozak, T.
  • Journal Title: Genes Volume: 10 Issue: 5 Pages: 367-367
  • DOI: 10.3390/genes10050367
  • Peer Reviewed / Open Access
• [Journal Article] Novel lineage-specific transmembrane β-barrel proteins in the endoplasmic reticulum of Entamoeba histolytica (2019)
  • Author(s): Santos HJ, Imai K, Makiuchi T, Tomii K, Horton P, Nozawa A, Okada K, Tozawa Y, Nozaki T
  • Journal Title: FEBS J Volume: 印刷中 Issue: 17 Pages: 3416-3432
  • DOI: 10.1111/febs.14870
  • Peer Reviewed / Open Access
• [Presentation] In silico search for genes having differentially localized protein isoforms via alternative splicing and alternative translation initiation (2020)
  • Author(s): Imai K, Yamada D.K
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] In silico search for mitochondrial proteins with differentially localized isoforms via alternative splicing and alternative translation initiation (2019)
  • Author(s): Imai, K., Fukasawa, Y., Yamada K.D
  • Organizer: the 16th ASMRM and 19th J-mit
  • Int'l Joint Research
• [Presentation] ミトコンドリアタンパク質輸送機構の多様な進化 (2018)
  • Author(s): 深沢 嘉紀、小田俊之、富井健太郎、今井賢一郎
  • Organizer: 第41回日本分子生物学会年会
• [Book] Encyclopedia of Bioinformatics and Computational Biology (Chapter: Prediction of Protein Localization) (2019)
  • Author(s): Imai K and Nakai K
  • Total Pages: 3284
  • Publisher: Elsevier Ltd
  • ISBN: 9780128114322