Molecular basis for membrane dynamics of phospholipids and its physiology & pathology

• Project/Area Number: 18H02615
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Osaka University
• Principal Investigator: Segawa Katsumori 大阪大学, 免疫学フロンティア研究センター, 特任准教授(常勤) (20542971)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
• Keywords: 細胞膜 / リン脂質 / フリッパーゼ / ホスファチジルセリン / フロッパーゼ / 細胞相互作用 / リン脂質移層分子 / 非対称性

Outline of Final Research Achievements

Biological membranes are composed of asymmetrically distributed phospholipid bilayers. For example, phosphatidylserine (PS) and phosphatidylethanolamine in cell membranes are localized in its inner leaflet. This asymmetric distribution of phospholipids is established and maintained by a dynamic equilibrium state of translocations of phospholipids across the lipid bilayers or between organelles. However, the mechanisms by which cells control this equilibrium of phospholipids and maintain the asymmetry of biological membranes are largely unknown. In this study, we elucidated the molecular mechanisms of the asymmetric distribution of PS, mainly regulated by phospholipid flippases.

Academic Significance and Societal Importance of the Research Achievements

本基盤研究により、細胞膜PSの非対称分布は、P4型ATPaseファミリーに属するフリッパーゼ、ATP11AとATP11Cにより維持されていることが明らかとなった。ATP11AとATP11Cは生理学・病態学的にも重要であった。ATP11A欠損マウスは胎生致死であり、ATP11C欠損マウスは生後にB細胞減少症、貧血、胆汁うっ滞症、難産などさまざまな病態を示す。また、ヒトにおいてもこれらのフリッパーゼに変異をもつ、重篤な疾患をしめす患者を見出した。本研究成果は、これらの疾患の病態の理解に貢献できると考えられる。

Research Products

• [Journal Article] Sensing and clearance of apoptotic cells (2021)
  • Author(s): Nagata Shigekazu、Segawa Katsumori
  • Journal Title: Current Opinion in Immunology Volume: 68 Pages: 1-8
  • DOI: 10.1016/j.coi.2020.07.007
  • Peer Reviewed
• [Journal Article] Transport Cycle of Plasma Membrane Flippase ATP11C by Cryo-EM (2020)
  • Author(s): Nakanishi Hanayo、Nishizawa Tomohiro、Segawa Katsumori、Nureki Osamu、Fujiyoshi Yoshinori、Nagata Shigekazu、Abe Kazuhiro
  • Journal Title: Cell Reports Volume: 32 Issue: 13 Pages: 108208-108208
  • DOI: 10.1016/j.celrep.2020.108208
  • Peer Reviewed / Open Access
• [Journal Article] Crystal structure of a human plasma membrane phospholipid flippase (2020)
  • Author(s): Nakanishi Hanayo、Irie Katsumasa、Segawa Katsumori、Hasegawa Kazuya、Fujiyoshi Yoshinori、Nagata Shigekazu、Abe Kazuhiro
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 30 Pages: 10180-10194
  • DOI: 10.1074/jbc.ra120.014144
  • Peer Reviewed / Open Access
• [Journal Article] Flippase and scramblase for phosphatidylserine exposure (2020)
  • Author(s): Nagata Shigekazu、Sakuragi Takaharu、Segawa Katsumori
  • Journal Title: Current Opinion in Immunology Volume: 62 Pages: 31-38
  • DOI: 10.1016/j.coi.2019.11.009
  • Peer Reviewed
• [Journal Article] Mechanisms for phosphatidylserine translocation and recognition of dead cells (2019)
  • Author(s): 瀬川 勝盛
  • Journal Title: 生化学 Volume: 91 Issue: 6 Pages: 743-752
  • DOI: 10.14952/SEIKAGAKU.2019.910743
  • NAID: 40022117166
  • ISSN: 0037-1017
  • Year and Date: 2019-12-25
  • Peer Reviewed
• [Journal Article] Functional Expression of the P2X7 ATP Receptor Requires Eros (2019)
  • Author(s): Ryoden Yuta、Fujii Toshihiro、Segawa Katsumori、Nagata Shigekazu
  • Journal Title: The Journal of Immunology Volume: 204 Issue: 3 Pages: 559-568
  • DOI: 10.4049/jimmunol.1900448
  • Peer Reviewed / Open Access
• [Journal Article] Predominant localization of phosphatidylserine at the cytoplasmic leaflet of the ER, and its TMEM16K-dependent redistribution (2019)
  • Author(s): Tsuji Takuma、Cheng Jinglei、Tatematsu Tsuyako、Ebata Aoi、Kamikawa Hiroki、Fujita Akikazu、Gyobu Sayuri、Segawa Katsumori、Arai Hiroyuki、Taguchi Tomohiko、Nagata Shigekazu、Fujimoto Toyoshi
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 27 Pages: 13368-13373
  • DOI: 10.1073/pnas.1822025116
  • Peer Reviewed / Open Access
• [Journal Article] リン脂質フリッパーゼとB細胞分化 (2019)
  • Author(s): 瀬川勝盛、長田重一
  • Journal Title: 臨床免疫・アレルギー科 Volume: 72 Pages: 80-86
  • NAID: 40021959396
• [Journal Article] MERTK tyrosine kinase receptor together with TIM4 phosphatidylserine receptor mediates distinct signal transduction pathways for efferocytosis and cell proliferation (2019)
  • Author(s): Nishi Chihiro、Yanagihashi Yuichi、Segawa Katsumori、Nagata Shigekazu
  • Journal Title: Journal of Biological Chemistry Volume: in press Issue: 18 Pages: 7221-7230
  • DOI: 10.1074/jbc.ra118.006628
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipid flippases enable precursor B cells to flee engulfment by macrophages (2018)
  • Author(s): Segawa Katsumori、Yanagihashi Yuichi、Yamada Kyoko、Suzuki Chigure、Uchiyama Yasuo、Nagata Shigekazu
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 48 Pages: 12212-12217
  • DOI: 10.1073/pnas.1814323115
  • Peer Reviewed
• [Presentation] 細胞膜の非対称性と脆弱性 (2021)
  • Author(s): 瀬川勝盛
  • Organizer: 千里ライフサイエンスセミナー P5 細胞死研究の新展開
  • Invited
• [Presentation] リン脂質が司る生命現象と疾患 (2020)
  • Author(s): 瀬川勝盛、領田優太、長田重一
  • Organizer: 第53回 生化学会
  • Invited
• [Presentation] Plasam membrane flippase: physiology & pathology (2020)
  • Author(s): 瀬川勝盛
  • Organizer: 東京医科歯科大学 難治疾患研究所 共同研究拠点研究集会 第一回細胞死 Colloquium
  • Invited
• [Presentation] Phospholipid asymmetry and plasma membrane phospholipid flippases (2018)
  • Author(s): katsumori Segawa
  • Organizer: Membrane Lipid Transporter Symposium 2018
  • Invited
• [Presentation] 細胞膜リン脂質の非対称性とフリッパーゼ (2018)
  • Author(s): 瀬川 勝盛
  • Organizer: 日本Cell Death学会学術集会
  • Invited
• [Presentation] Plasma membrane phospholipid asymmetry and phospholipid flippases (2018)
  • Author(s): Katsumori Segawa
  • Organizer: Frontiers in P-type ATPase Research 2018
  • Invited
• [Book] 脂質クオリティ (2018)
  • Author(s): 有田 誠
  • Total Pages: 220
  • Publisher: 羊土社
  • ISBN: 9784758103718
• [Remarks] 研究室HP
  • URL: http://biochemi.ifrec.osaka-u.ac.jp/