Elucidation of the mechanism of non-cell death caspase activation that determines the phenotype of each individual.

• Project/Area Number: 21H04774
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 44:Biology at cellular to organismal levels, and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Miura Masayuki 東京大学, 大学院薬学系研究科(薬学部), 教授 (50202338)
• Project Period (FY): 2021-04-05 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥41,600,000 (Direct Cost: ¥32,000,000、Indirect Cost: ¥9,600,000); Fiscal Year 2023: ¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000); Fiscal Year 2022: ¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000); Fiscal Year 2021: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
• Keywords: カスパーゼ / 非アポトーシス / 表現度 / 個体差 / ショウジョウバエ / 非細胞死 / 遺伝学

Outline of Research at the Start

個体ごとに身長や疾患感受性といった表現型に強弱が現れるが、その違い（表現度：expressivity）を生み出す機構は殆どが不明である。我々はカスパーゼの非アポトーシス機能としての基質プロセッシング(Basal Caspase Processing: BCP)が表現度に関わる知見を得ている。本研究では新たな技術を導入し、カスパーゼ作用「場」の包括的分子同定によってこれまで未知のBCP 活性化プラットフォームとその作用メカニズムを遺伝学的、生化学的に明らかにすることで表現度の制御機構を明らかにすることを目指す。

Outline of Final Research Achievements

Expressivity of phenotype is regulated by Basal Caspase Processing (BCP) which is mediated through non cell death inducing caspase activity. However, the regulation of BCP is still unknown and genome-wide analysis of BCP has not been conducted yet. We performed the analysis of caspase-proximal proteins in Drosophila brain and identified the cell adhesion molecule Fasciclin 3 (Fas3) as a molecule that promotes caspase activation upon its overexpression. We performed genome-wide screening of genes involved in the BCP-regulated expressivity of sensory bristle numbers using the GWAS method.

Academic Significance and Societal Importance of the Research Achievements

生理機能やストレス応答、薬剤への感受性、寿命といった表現型の程度は個体ごとに異なる。表現度は注目する表現型の個体間の強弱を示すが、BCPの制御機構の研究によって表現度制御の分子メカニズムの解明が進むと、疾患や老化といった個体差の大きな現象の理解を深めることが期待される。

Research Products

• [Journal Article] Mating-induced increase of kynurenine in Drosophila ovary enhances starvation resistance of progeny (2024)
  • Author(s): Hikawa Naoto、Kashio Soshiro、Miura Masayuki
  • Journal Title: Journal of Biological Chemistry Volume: 300 Issue: 3 Pages: 105663-105663
  • DOI: 10.1016/j.jbc.2024.105663
  • Peer Reviewed
• [Journal Article] Epidermal tyrosine catabolism is crucial for metabolic homeostasis and survival against high-protein diets in <i>Drosophila</i> (2024)
  • Author(s): Kosakamoto Hina、Miura Masayuki、Obata Fumiaki
  • Journal Title: Development Volume: 151 Issue: 1
  • DOI: 10.1242/dev.202372
  • Peer Reviewed / Open Access
• [Journal Article] Distinct stem-like cell populations facilitate functional regeneration of the Cladonema medusa tentacle (2023)
  • Author(s): Fujita Sosuke、Takahashi Mako、Kumano Gaku、Kuranaga Erina、Miura Masayuki、Nakajima Yu-ichiro
  • Journal Title: PLOS Biology Volume: 21 Issue: 12 Pages: e3002435-e3002435
  • DOI: 10.1371/journal.pbio.3002435
  • Peer Reviewed / Open Access
• [Journal Article] Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila (2023)
  • Author(s): Kosakamoto Hina、Obata Fumiaki、Kuraishi Junpei、Aikawa Hide、Okada Rina、Johnstone Joshua N.、Onuma Taro、Piper Matthew D. W.、Miura Masayuki
  • Journal Title: Nature Communications Volume: 14 Issue: 1 Pages: 7832-7832
  • DOI: 10.1038/s41467-023-43550-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nutrient-driven dedifferentiation of enteroendocrine cells promotes adaptive intestinal growth in Drosophila (2023)
  • Author(s): Nagai Hiroki、Nagai Luis Augusto Eijy、Tasaki Sohei、Nakato Ryuichiro、Umetsu Daiki、Kuranaga Erina、Miura Masayuki、Nakajima Yuichiro
  • Journal Title: Developmental Cell Volume: 58 Issue: 18 Pages: 1764-1781.e10
  • DOI: 10.1016/j.devcel.2023.08.022
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of neuronal tachykinin-like receptor at 86C in Drosophila disc repair via regulation of kynurenine metabolism (2023)
  • Author(s): Kashio Soshiro、Masuda Shu、Miura Masayuki
  • Journal Title: iScience Volume: 26 Issue: 9 Pages: 107553-107553
  • DOI: 10.1016/j.isci.2023.107553
  • Peer Reviewed / Open Access
• [Journal Article] Caspase cleaves<i>Drosophila</i><scp>BubR1</scp>to modulate spindle assembly checkpoint function and lifespan of the organism (2023)
  • Author(s): Shinoda Natsuki、Horikoshi Misuzu、Taira Yusuke、Muramoto Masaya、Hirayama Shoshiro、Murata Shigeo、Miura Masayuki
  • Journal Title: The FEBS Journal Volume: 290 Issue: 17 Pages: 4200-4223
  • DOI: 10.1111/febs.16811
  • Peer Reviewed / Open Access
• [Journal Article] Damage sensing mediated by serine proteases Hayan and Persephone for Toll pathway activation in apoptosis-deficient flies (2023)
  • Author(s): Nakano Shotaro、Kashio Soshiro、Nishimura Kei、Takeishi Asuka、Kosakamoto Hina、Obata Fumiaki、Kuranaga Erina、Chihara Takahiro、Yamauchi Yoshio、Isobe Toshiaki、Miura Masayuki
  • Journal Title: PLOS Genetics Volume: 19 Issue: 6 Pages: e1010761-e1010761
  • DOI: 10.1371/journal.pgen.1010761
  • Peer Reviewed / Open Access
• [Journal Article] Methionine metabolism regulates pluripotent stem cell pluripotency and differentiation through zinc mobilization (2022)
  • Author(s): Sim Z.E, Enomoto T, Shiraki N, Furuta N, Kashio S, Kambe T. Tsuyama T. Arakawa A, Ozawa H. Yokoyama M, Miura M, Kume S
  • Journal Title: Cell Reports Volume: 40 Issue: 3 Pages: 111120-111120
  • DOI: 10.1016/j.celrep.2022.111120
  • Peer Reviewed / Open Access
• [Journal Article] Sensing of the non-essential amino acid tyrosine governs the response to protein restriction in Drosophila (2022)
  • Author(s): Kosakamoto Hina、Okamoto Naoki、Aikawa Hide、Sugiura Yuki、Suematsu Makoto、Niwa Ryusuke、Miura Masayuki、Obata Fumiaki
  • Journal Title: Nature Metabolism Volume: 4 Issue: 7 Pages: 944-959
  • DOI: 10.1038/s42255-022-00608-7
  • Peer Reviewed / Open Access
• [Journal Article] Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase (2022)
  • Author(s): Mizuno Rin、Hojo Hiroaki、Takahashi Masatomo、Kashio Soshiro、Enya Sora、Nakao Motonao、Konishi Riyo、Yoda Mayuko、Harata Ayano、Hamanishi Junzo、Kawamoto Hiroshi、Mandai Masaki、Suzuki Yutaka、Miura Masayuki、Bamba Takeshi、Izumi Yoshihiro、Kawaoka Shinpei
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 3346-3346
  • DOI: 10.1038/s41467-022-30926-z
  • Peer Reviewed / Open Access
• [Journal Article] Biosynthesis of S-adenosyl-methionine enhances aging-related defects in Drosophila oogenesis (2022)
  • Author(s): Hayashi Yoshiki、Kashio Soshiro、Murotomi Kazutoshi、Hino Shinjiro、Kang Woojin、Miyado Kenji、Nakao Mitsuyoshi、Miura Masayuki、Kobayashi Satoru、Namihira Masakazu
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 1-9
  • DOI: 10.1038/s41598-022-09424-1
  • Peer Reviewed / Open Access
• [Journal Article] Caspase-3 regulates ureteric branching in mice via cell migration (2021)
  • Author(s): Awazu Midori、Yamaguchi Yoshifumi、Nagata Michio、Miura Masayuki、Hida Mariko
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 559 Pages: 28-34
  • DOI: 10.1016/j.bbrc.2021.04.081
  • Peer Reviewed
• [Journal Article] Hepatic resistance to cold ferroptosis in a mammalian hibernator Syrian hamster depends on effective storage of diet-derived α-tocopherol (2021)
  • Author(s): Anegawa Daisuke、Sugiura Yuki、Matsuoka Yuta、Sone Masamitsu、Shichiri Mototada、Otsuka Reo、Ishida Noriko、Yamada Ken-ichi、Suematsu Makoto、Miura Masayuki、Yamaguchi Yoshifumi
  • Journal Title: Communications Biology Volume: 4 Issue: 1 Pages: 796-796
  • DOI: 10.1038/s42003-021-02297-6
  • Peer Reviewed / Open Access
• [Journal Article] Evidence for the involvement of caspases in establishing proper cerebrospinal fluid hydrodynamics (2021)
  • Author(s): Yoshida Ayako、Kawata Daisuke、Shinotsuka Naomi、Yoshida Mariko、Yamaguchi Yoshifumi、Miura Masayuki
  • Journal Title: Neuroscience Research Volume: 170 Pages: 145-153
  • DOI: 10.1016/j.neures.2020.12.006
  • Peer Reviewed
• [Journal Article] Activation of innate immunity during development induces unresolved dysbiotic inflammatory gut and shortens lifespan (2021)
  • Author(s): Yamashita Kyoko、Oi Ayano、Kosakamoto Hina、Yamauchi Toshitaka、Kadoguchi Hibiki、Kuraishi Takayuki、Miura Masayuki、Obata Fumiaki
  • Journal Title: Disease Models & Mechanisms Volume: 14 Issue: 9 Pages: 49103-49103
  • DOI: 10.1242/dmm.049103
  • Peer Reviewed
• [Presentation] Non-lethal caspase activation in aged Drosophila olfactory neurons. (2023)
  • Author(s): M. Miura
  • Organizer: Japan Australia Meeting on Cell Death
  • Int'l Joint Research / Invited
• [Presentation] カスパーゼ生体機能の探索 (2023)
  • Author(s): 三浦正幸
  • Organizer: 第３１回日本Cell Death学会学術集会
  • Invited
• [Presentation] Dual FRETシステムを基盤とした細胞内局所的カスパーゼ活性の解析 (2023)
  • Author(s): 平雄介、篠田夏樹、三浦正幸
  • Organizer: 第75回日本細胞生物学会学術集会
• [Presentation] カスパーゼは紡錘体チェックポイント構成因子BubR1を切断し, ショウジョウバエ個体の寿命を制限する (2023)
  • Author(s): 篠田夏樹、堀越水涼、平雄介、村本雅哉、平山尚志郎、村田茂穂、三浦正幸
  • Organizer: 第31回日本Cell Death学会学術集会
• [Presentation] 個体老化を制御する栄養感受性臨界期の存在 (2022)
  • Author(s): 三浦正幸
  • Organizer: 第４１回日本認知症学学術集会、第３７回日本老年精神医学会合同開催
  • Invited
• [Presentation] アポトーシスにおける細胞内局所的カスパーゼ活性の解析 (2022)
  • Author(s): 平雄介、篠田夏樹、三浦正幸
  • Organizer: 第74回日本細胞生物学会
• [Presentation] 生体膜に限局した非細胞死性カスパーゼ反応場の発見とその機能解析 (2022)
  • Author(s): 村本雅哉、花輪望未、篠田夏樹、三浦正幸
  • Organizer: 第30回 日本Cell Death学会学術集会
• [Presentation] Genetic control of animal aging by amino acids metabolism (2021)
  • Author(s): Masayuki Miura
  • Organizer: 第44回日本基礎老化学会大会国際シンポジウム
  • Invited
• [Presentation] 代謝による個体老化の臨界期制御 (2021)
  • Author(s): 三浦正幸
  • Organizer: 第64回日本神経化学会大会シンポジウム
  • Invited