Activation mechanism of unfolded protein response by membrane lipid saturation

• Project/Area Number: 25460060
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: Kono Nozomu 東京大学, 薬学研究科(研究院), 講師 (50451852)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: リン脂質 / 脂肪酸 / 小胞体ストレス応答

Outline of Final Research Achievements

Increased levels of saturated fatty acids in membrane phospholipids (membrane lipid saturation) activated IRE1α and PERK, but did not activate ATF6α. A conventional ER stressor induced clustering of fluorescently tagged IRE1α fusion protein, but membrane lipid saturation did not. These results suggest membrane lipid saturation and unfolded proteins activate the UPR through different mechanisms. Analysis of an ER membrane protein involved in the UPR activation upon membrane lipid saturation revealed a homeostatic mechanism against membrane lipid saturation.

Research Products

• [Journal Article] Phosphatidic acid induces EHD3-containing membrane tubulation and is required for receptor recycling. Exp. Cell Res. 342, 1-10. (2016)
  • Author(s): Henmi, Y., Oe, N., Kono, N., Taguchi, T., Takei, K., and Tanabe, K.
  • Journal Title: Exp. Cell Res. Volume: 342 Issue: 1 Pages: 1-10
  • DOI: 10.1016/j.yexcr.2016.02.011
  • Peer Reviewed
• [Journal Article] Age-related changes of vitamin E: α-tocopherol levels in plasma and various tissues of mice and hepatic α-tocopherol transfer protein. (2016)
  • Author(s): Takahashi, K., Takisawa, S., Shimokado, K., Kono, N., Arai, H., Ishigami, A.
  • Journal Title: Eur J Nutr. Volume: 印刷中 Issue: 3 Pages: 1317-1327
  • DOI: 10.1007/s00394-016-1182-4
  • Peer Reviewed
• [Journal Article] Lysophosphatidylcholine acyltransferase 1 protects against cytotoxicity induced by polyunsaturated fatty acids. (2016)
  • Author(s): Akagi, S., Kono, N., Ariyama, H., Shindou, H., Shimizu, T., and Arai, H.
  • Journal Title: FASEB J. Volume: 30 Issue: 5 Pages: 2027-2039
  • DOI: 10.1096/fj.201500149
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Intracellular Platelet-Activating Factor Acetylhydrolase, Type II: A Unique Cellular Phospholipase A2 That Hydrolyzes Oxidatively Modified Phospholipids. (2015)
  • Author(s): Kono N, Arai H.
  • Journal Title: Enzymes Volume: 38 Pages: 43-54
  • DOI: 10.1016/bs.enz.2015.09.008
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Neurite outgrowth stimulation by n3 and n6 polyunsaturated fatty acids of phospholipids in apolipoprotein E containing lipoproteins secreted from glial cells. (2015)
  • Author(s): Nakato M, Matsuo M, Kono N, Arita M, Arai H, Ogawa J, Kioka N, Ueda K.
  • Journal Title: J Lipid Res Volume: 56 Issue: 10 Pages: 1880-1890
  • DOI: 10.1194/jlr.m058164
  • Peer Reviewed / Open Access
• [Journal Article] Interaction of Phospholipase A/acyltransferase-3 with Pex19p: a Possible Involvement in the Downregulation of Peroxisomes (2015)
  • Author(s): Toru Uyama, Katsuhisa Kawai, Nozomu Kono, Masahiro Watanabe, Kazuhito Tsuboi, Tomohito Inoue, Nobukazu Araki, Hiroyuki Arai, and Natsuo Ueda
  • Journal Title: Journal of Biological Chemistry Volume: 290 Issue: 28 Pages: 17520-17534
  • DOI: 10.1074/jbc.m114.635433
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 脂質異常とオルガネラストレス (2015)
  • Author(s): 大場陽介、河野望
  • Journal Title: 医学のあゆみ Volume: 254 Pages: 382-388
• [Journal Article] リン脂質脂肪酸鎖メタボロームと代謝疾患 (2015)
  • Author(s): 大場陽介、河野望、新井洋由
  • Journal Title: 内分泌・糖尿病・代謝内科 Volume: 41 Pages: 341-346
• [Journal Article] 飽和脂肪酸による小胞体ストレス応答の活性化 (2015)
  • Author(s): 河野 望、新井 洋由
  • Journal Title: BIO Clinica Volume: 30 Pages: 737-741
• [Journal Article] ABCB4 exports phosphatidylcholine in a sphingomyelin-dependent manner (2015)
  • Author(s): Zhao, Y., Ishigami, M., Nagao, K., Hanada, K., Kono, N., Arai, H., Matsuo, M., Kioka, N., and Ueda, K.
  • Journal Title: J. Lipid Res. Volume: 56 Issue: 3 Pages: 644-652
  • DOI: 10.1194/jlr.m056622
  • Peer Reviewed
• [Journal Article] Stearoyl-CoA desaturase 1 activity is required for autophagosome formation. (2014)
  • Author(s): Ogasawara Y, Itakura E, Kono N, Mizushima N, Arai H, Nara A, Mizukami T, Yamamoto A.
  • Journal Title: J Biol Chem Volume: 289 Issue: 34 Pages: 23938-23950
  • DOI: 10.1074/jbc.m114.591065
  • Peer Reviewed
• [Journal Article] Intracellular transport of fat-soluble vitamins A and E. (2014)
  • Author(s): Kono N, Arai H.
  • Journal Title: Traffic Volume: 16 Issue: 1 Pages: 19-34
  • DOI: 10.1111/tra.12231
  • Peer Reviewed / Open Access
• [Journal Article] ビタミンE特異的輸送タンパク質α-TTPによる体内ビタミンEレベルの制御 (2014)
  • Author(s): 河野 望、新井 洋由
  • Journal Title: 生化学 Volume: 86 Pages: 232-241
  • NAID: 40020096185
  • Peer Reviewed
• [Journal Article] 膜脂質飽和化による小胞体ストレス応答の活性化 (2014)
  • Author(s): 河野 望、新井 洋由
  • Journal Title: 実験医学 Volume: 32 Pages: 2208-2213
  • Peer Reviewed
• [Journal Article] 脂質輸送タンパク質による細胞内脂質輸送機構の最前線 (2014)
  • Author(s): 河野 望、新井 洋由
  • Journal Title: ファルマシア Volume: 134 Pages: 290-294
  • NAID: 130005154886
  • Peer Reviewed
• [Journal Article] Identification of genes and pathways involved in the synthesis of Meadacid (20:3n-9), an indicator of essential fatty acid deficiency. (2014)
  • Author(s): Ichi I, Kono N, Arita Y, Haga S, Arisawa K, Yamano M, Nagase M, Fujiwara Y, Arai H
  • Journal Title: biochim Biophys Acta Volume: 1841 Issue: 1 Pages: 204-213
  • DOI: 10.1016/j.bbalip.2013.10.013
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ビタミンE輸送タンパク質とホスファチジルイノシトールリン酸との相互作用不全が家族性ビタミンE欠乏症の原因となる (2014)
  • Author(s): 河野 望, 大戸 梅治, 平松 達史, 卜部 倫子, 内田 安則, 佐藤 能雅, 新井 洋由
  • Journal Title: ビタミン Volume: 88 Pages: 148-150
• [Journal Article] 飽和脂肪酸と小胞体ストレス応答 (2014)
  • Author(s): 河野 望, 新井 洋由
  • Journal Title: 医学のあゆみ Volume: 248 Pages: 1178-1183
• [Journal Article] Impaired α-TTP-PIPs interaction underlies familial vitamin E deficiency. (2013)
  • Author(s): Kono N, Ohto U, Hiramatsu T, Urabe M, Uchida Y, Satow Y, Arai H.
  • Journal Title: Science Volume: 340 Issue: 6136 Pages: 1106-1110
  • DOI: 10.1126/science.1233508
  • NAID: 110009807290
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Membrane lipidsaturation activates IRE1α without clustering (2013)
  • Author(s): Yuto Kitai, Hiroyuki Ariyama, Nozomu Kono, Daisuke Oikawa, Takao Iwawaki, Hiroyuki Arai
  • Journal Title: Genes Cells Volume: 18 Issue: 9 Pages: 798-809
  • DOI: 10.1111/gtc.12074
  • Peer Reviewed
• [Journal Article] Saturated fatty acid palmitate aggravates neointima formation by promoting smooth muscle phenotypic modulation. (2013)
  • Author(s): Shen H, Eguchi K, Kono N, Fujiu K, Matsumoto S, Shibata M, Oishi-Tanaka Y, Komuro I, Arai H, Nagai R, Manabe I.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 33 Pages: 2596-2607
  • Peer Reviewed
• [Journal Article] Mitochondria-type GPAT is required for mitochondrial fusion (2013)
  • Author(s): Yohsuke Ohba, Takeshi Sakuragi, Eriko Kage-Nakadai, Naoko H Tomioka, Nozomu Kono, Rieko Imae, Asuka Inoue, Junken Aoki, Naotada Ishihara, Takao Inoue, Shohei Mitani and Hiroyuki Arai
  • Journal Title: The EMBO Journal Volume: (in press) Issue: 9 Pages: 1265-1279
  • DOI: 10.1038/emboj.2013.77
  • Peer Reviewed / Open Access
• [Journal Article] Identification of small subunit of serine palmitoyltransferase a as a lysophosphatidylinositol acyltransferase 1-interacting protein. (2013)
  • Author(s): Hirata Y, Yamamori N, Kono N, Lee HC, Inoue T, Arai H.
  • Journal Title: Genes Cells. Volume: 18 Issue: 5 Pages: 397-409
  • DOI: 10.1111/gtc.12046
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 生体膜リン脂質脂肪酸鎖の多様性形成・維持機構とその破綻 (2013)
  • Author(s): 河野 望, 新井 洋由
  • Journal Title: 内分泌・糖尿病・代謝内科 Volume: 36 Pages: 479-484
• [Journal Article] 細胞内ビタミンE輸送におけるホスファチジルイノシトールリン酸の役割 (2013)
  • Author(s): 河野 望, 新井 洋由
  • Journal Title: 細胞工学 Volume: 32 Pages: 1072-1074
• [Presentation] LPCAT1はPUFAによる細胞毒性を抑制する (2015)
  • Author(s): 赤木 聡介, 河野 望, 有山 博之, 新井 洋由
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド、兵庫
  • Year and Date: 2015-12-01
• [Presentation] 小胞体ストレス応答分子IRE1を介した膜脂肪酸ストレス応答機構の解明 (2015)
  • Author(s): 大場陽介、河野望、新井洋由
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド、兵庫
  • Year and Date: 2015-12-01
• [Presentation] SREBP経路を介した飽和脂肪酸毒性の防御機構 (2015)
  • Author(s): 菅原 礼、中村 将吾、河野 望、新井 洋由
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド、兵庫
  • Year and Date: 2015-12-01
• [Presentation] IRE1の活性化依存的に結合・解離するIRE1結合タンパク質の同定 (2015)
  • Author(s): 北井 祐人, 河野 望, 岩脇 隆夫, 鈴木 健裕, 堂前 直, 新井 洋由
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド、兵庫
  • Year and Date: 2015-12-01
• [Presentation] LPCAT1はPUFAによる細胞毒性を抑制する (2015)
  • Author(s): 赤木 聡介, 河野 望, 有山 博之, 新井 洋由
  • Organizer: フォーラム2015 衛生薬学・環境トキシコロジー
  • Place of Presentation: 神戸学院大学 ポートアイランドキャンパス、兵庫
  • Year and Date: 2015-09-17
• [Presentation] 飽和脂肪酸含有リン脂質による炎症・ストレス応答の誘導 (2015)
  • Author(s): 栗原 大輔，河野 望，新井 洋由
  • Organizer: フォーラム2015 衛生薬学・環境トキシコロジー
  • Place of Presentation: 神戸学院大学 ポートアイランドキャンパス、兵庫
  • Year and Date: 2015-09-17
• [Presentation] 飽和脂肪酸毒性の新規抑制因子の同定 (2015)
  • Author(s): 菅原 礼、中村 将吾、河野 望、新井 洋由
  • Organizer: 第14回 次世代を担う若手ファーマ・バイオフォーラム2015
  • Place of Presentation: 千葉大学亥鼻キャンパス 医薬系総合研究棟 (薬学研究院)、千葉
  • Year and Date: 2015-09-12
• [Presentation] Lysophosphatidylcholine acyltransferase 1 protects against cytotoxicity induced by polyunsaturated fatty acids (2015)
  • Author(s): 赤木 聡介, 河野 望, 有山 博之, 新井 洋由
  • Organizer: 第15回 東京大学 生命科学シンポジウム
  • Place of Presentation: 東京大学安田講堂 東京
  • Year and Date: 2015-06-07
• [Presentation] 飽和脂肪酸含有リン脂質による炎症・ストレス応答の誘導 (2015)
  • Author(s): 栗原 大輔，河野 望，新井 洋由
  • Organizer: 第15回 東京大学 生命科学シンポジウム
  • Place of Presentation: 東京大学安田講堂 東京
  • Year and Date: 2015-06-07
• [Presentation] 小胞体ストレス応答分子IRE1を介した膜脂肪酸ストレス応答機構 (2015)
  • Author(s): 大場陽介、河野望、新井洋由
  • Organizer: 第57回日本脂質生化学会
  • Place of Presentation: 一橋講堂、東京
  • Year and Date: 2015-05-28
• [Presentation] Unfolded protein response is differently activated by membrane lipid saturation and unfolded proteins in the endoplasmic reticulum (2015)
  • Author(s): Yuto Kitai, Hiroyuki Ariyama, Nozomu Kono, Daisuke Oikawa, Takao Iwawaki, Hiroyuki Arai
  • Organizer: Keystone Symposia meeting The Crossroads of Lipid Metabolism and Diabetes
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2015-04-19
  • Int'l Joint Research
• [Presentation] The role of type II PAF acetylhydrolase in IgE-mediated mast cell activation (2015)
  • Author(s): Nozomu Kono, Yuta Shimanaka, Yoshitaka Taketomi, Makoto Murakami, and Hiroyuki Arai
  • Organizer: 6th International Conference Phospholipase A2 and Lipid Mediators
  • Place of Presentation: Tokyo
  • Year and Date: 2015-02-10 – 2015-02-15
• [Presentation] Role of α-TTP-PIPs Interaction in intracellular vitamin E transport (2015)
  • Author(s): Nozomu Kono, Umeharu Ohoto, and Hiroyuki Arai
  • Organizer: 6th International Conference Phospholipase A2 and Lipid Mediators
  • Place of Presentation: Tokyo
  • Year and Date: 2015-02-10 – 2015-02-15
• [Presentation] Unfolded protein response is differently activated by membrane lipid saturation and unfolded proteins in the endoplasmic reticulum (2015)
  • Author(s): Yuto Kitai, Hiroyuki Ariyama, Nozomu Kono, Daisuke Oikawa, Takao Iwawaki, and Hiroyuki Arai
  • Organizer: 6th International Conference Phospholipase A2 and Lipid Mediators
  • Place of Presentation: Tokyo
  • Year and Date: 2015-02-10 – 2015-02-15
• [Presentation] 酸化リン脂質選択的ホスホリパーゼA2のマスト細胞脱顆粒シグナルにおける機能 (2014)
  • Author(s): 河野 望、嶋中 雄太、武富 芳隆、村上 誠、新井 洋由
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] 飽和脂肪酸毒性に関与する新規因子の同定 (2014)
  • Author(s): 中村 将吾、有山 博之、菅原 礼、河野 望、新井 洋由
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] Unfolded protein response is differently activated by membrane lipid saturation and unfolded proteins in the endoplasmic reticulum (2014)
  • Author(s): Nozomu Kono, Yuto Kitai, Hiroyuki Ariyama, Daisuke Oikawa, Takao Iwawaki, and Hiroyuki Arai
  • Organizer: 2014 FASEB Summer Research Conference: Phospholipid Cell Signaling and Metabolism in Inflammation and Cancer
  • Place of Presentation: Niagara falls, NY, USA
  • Year and Date: 2014-06-01 – 2014-06-06
• [Presentation] 細胞内ビタミンE輸送におけるPIP2脂肪酸鎖の役割 (2014)
  • Author(s): 河野 望，新井 洋由
  • Organizer: 第25回ビタミンE研究会
  • Place of Presentation: 鳥取県米子市
• [Presentation] 膜脂肪酸飽和化と異常タンパク質蓄積による小胞体ストレス応答の違い (2013)
  • Author(s): 北井 祐人, 有山 博之, 河野 望, 新井 洋由
  • Organizer: 第55回 日本脂質生化学会
  • Place of Presentation: 宮城県松島町
• [Presentation] 膜脂肪酸飽和化と異常タンパク質蓄積による小胞体ストレス応答の違い (2013)
  • Author(s): 北井祐人, 有山博之, 河野望, 新井洋由
  • Organizer: 第13回東京大学生命化学シンポジウム
  • Place of Presentation: 東京都文京区
• [Presentation] 膜脂肪酸飽和化と異常タンパク質蓄積による小胞体ストレス応答の違い (2013)
  • Author(s): 北井祐人, 有山博之, 河野望, 新井洋由
  • Organizer: 平成25年度 日本生化学会関東支部例会
  • Place of Presentation: 山梨県中央市
• [Presentation] α-TTPを介した肝細胞内ビタミンE輸送におけるPIPsの役割 (2013)
  • Author(s): 河野 望, 大戸 梅治, 佐藤 能雅, 新井 洋由
  • Organizer: 第55回 日本脂質生化学会
  • Place of Presentation: 宮城県松島町
• [Presentation] Role of α-TTP-PIPs Interaction in intracellular vitamin E transport (2013)
  • Author(s): Nozomu Kono, Umeharu Ohto, Yoshinori Satow and Hiroyuki Arai
  • Organizer: 2013 Gordon Research Conference
  • Place of Presentation: Waterville Valley, NH, United States
• [Presentation] 小胞体ストレス応答タンパク質IRE-1を介した飽和脂肪酸代謝制御 (2013)
  • Author(s): 河野 望, 新井 洋由
  • Organizer: 第86回 日本生化学会大会
  • Place of Presentation: 神奈川県横浜市
  • Invited
• [Presentation] 膜脂肪酸飽和化と異常タンパク質蓄積による小胞体ストレス応答の違い (2013)
  • Author(s): 北井祐人, 有山博之, 河野望, 新井洋由
  • Organizer: 第86回 日本生化学会大会
  • Place of Presentation: 神奈川県横浜市
• [Presentation] ビタミンEの肝細胞内輸送機構と先天性欠乏症 (2013)
  • Author(s): 河野 望，新井 洋由
  • Organizer: フォーラム2013 衛生薬学・環境トキシコロジー
  • Place of Presentation: 福岡県福岡市
  • Invited
• [Presentation] 膜脂肪酸飽和化と異常タンパク質蓄積による小胞体ストレス応答の違い (2013)
  • Author(s): 中村 将吾，北井 祐人，有山 博之，河野 望，新井 洋由
  • Organizer: フォーラム2013 衛生薬学・環境トキシコロジー
  • Place of Presentation: 福岡県福岡市
• [Remarks] 東京大学大学院薬学系研究科衛生化学
  • URL: https://sites.google.com/site/eiseikagaku/