Maintenance of the endoplasmic reticulum function by the unfolded protein response (UPR)

• Project Area: Protein community: organization and maintenance of protein functions
• Project/Area Number: 19058009
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: MORI Kazutoshi 京都大学, 大学院・理学研究科, 教授 (70182194)
• Co-Investigator(Kenkyū-buntansha): 森 博幸 京都大学, ウイルス研究所, 准教授 (10243271)
• Project Period (FY): 2007 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥119,200,000 (Direct Cost: ¥119,200,000); Fiscal Year 2011: ¥26,400,000 (Direct Cost: ¥26,400,000); Fiscal Year 2010: ¥26,400,000 (Direct Cost: ¥26,400,000); Fiscal Year 2009: ¥26,400,000 (Direct Cost: ¥26,400,000); Fiscal Year 2008: ¥26,400,000 (Direct Cost: ¥26,400,000); Fiscal Year 2007: ¥13,600,000 (Direct Cost: ¥13,600,000)
• Keywords: 小胞体 / 高次構造形成 / 分子シャペロン / タンパク質分解 / 品質管理 / 転写誘導 / 翻訳抑制 / 遺伝子ノックアウト / メダカ / 初期発生 / 脊索 / ニワトリ細胞 / オルガネラ / スプライシング / 翻訳 / 転写 / 脂質 / プロテアソーム / 分解 / フォールディング / 転写透導 / オルガネラ形成 / 生体膜 / リン脂質 / B細胞分化

Research Abstract

We discovered that unfolded proteins accumulate in the endoplasmic reticulum (ER) of the notochord during medaka early embryonic development, that medaka refolds the accumulated unfolded proteins by activating sensor proteins designated ATF6α and ATF6β and thereby inducing ER-localized molecular chaperones, and that medaka deficient in both ATF6α and ATF β dies due to notochord abnormality. Thus, the unfolded protein response plays a critical role in the homeostasis of the cell and body.

Research Products

• [Journal Article] A thrombospondin-dependent pathway for a protective ER stress response (2012)
  • Author(s): J. M. Lynch, M. Maillet, D. Vanhoutte, A. Schloemer, M. A. Sargent, N. S. Blair, K. A. Lynch, T. Okada, B. J. Aronow, H. Osinska, R. Prywes, J. N. Lorenz, K. Mori, J. Lawler, J. Robbins and J. D. Molkentin
  • Journal Title: Cell Volume: (in press)
  • Peer Reviewed
• [Journal Article] A novel IFN-γ-stimulated ATF6/C/EBP-β signaling pathway critical for the expression of DAPK 1 and induction of autophagy (2012)
  • Author(s): P. Gade, G. Ramachandran, U.B. Maachani, M.A. Rizzo, T. Okada, R. Prywes, A.S. Cross. K. Mori and D. J. Kalvakolanu
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: (in press)
  • Peer Reviewed
• [Journal Article] The Specialized Unfolded Protein Response of B Lymphocytes: ATF6α-Independent Development of Antibody-Secreting B cells (2012)
  • Author(s): I. V. Aragon, R. A. Barrington, S. Jackowski, K. Mori and J. W. Brewer
  • Journal Title: Mol. Immunol. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. (2012)
  • Author(s): M. Usui, S. Yamaguchi, Y. Tanji, R. Tominaga, Y. Ishigaki, M. Fukumoto, H. Katagiri, K. Mori, Y. Oka and H. Ishihara
  • Journal Title: Metabol. Volume: (in press)
  • Peer Reviewed
• [Journal Article] ER stress activates the NLRP3 inflammasome via an UPR-independent pathway (2012)
  • Author(s): P. Menu, A. Mayor, R. Zhou, A. Tardivel, H. Ichijo, K. Mori and J. Tschopp
  • Journal Title: Cell Death Dis. Volume: 3 Issue: 1 Pages: e261-e261
  • DOI: 10.1038/cddis.2011.132
  • Peer Reviewed
• [Journal Article] Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance (2012)
  • Author(s): M.Usui, S.Yamaguchi, Y.Tanji, R.Tominaga, Y.Ishigaki, M.Fukumoto, H.Katagiri, K.Mori, Y.Oka, H.Ishihara
  • Journal Title: Metabol Volume: (in press) Issue: 8 Pages: 1118-28
  • DOI: 10.1016/j.metabol.2012.01.004
  • Peer Reviewed
• [Journal Article] Vertebrate Unfolded Protein Response: Mammalian Signaling Pathways Are Conserved in Medaka Fish (2011)
  • Author(s): Tokiro Ishikawa, Yoshihito Taniguchi, Tetsuya Okada, Shunichi Takeda, Kazutoshi Mori
  • Journal Title: Cell Structure and Function Volume: 36 Issue: 2 Pages: 247-259
  • DOI: 10.1247/csf.11036
  • NAID: 130004137573
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed
• [Journal Article] SEL1L Is Required for Endoplasmic Reticulum-associated Degradation of Misfolded Luminal Proteins but not Transmembrane Proteins in Chicken DT40 Cell Line (2011)
  • Author(s): S. Ninagawa, T. Okada, S. Takeda and K. Mori
  • Journal Title: Cell Structure and Function Volume: 36 Issue: 2 Pages: 187-195
  • DOI: 10.1247/csf.11018
  • NAID: 130004137570
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed
• [Journal Article] Endoplasmic reticulum stress increases the expression and function of toll-like receptor-2 in epithelial cells. (2010)
  • Author(s): S.Shimasaki, T.Koga, T.Shuto, MA.Suico, T.Sato, K.Watanabe, S.Morino-Koga, M.Taura, S.Okada, K.Mori, H.Kai
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 402 Pages: 235-240
  • Peer Reviewed
• [Journal Article] The endoplasmic reticulum stress sensor, ATF6α, protects against neurotoxin-induced dopaminergic neuronal death. (2010)
  • Author(s): N.Egawa, K.Yamamoto, H.Inoue, R.Hikawa, K.Nishi, K.Mori, R.Takahashi
  • Journal Title: J.Biol.Chem. Volume: 286 Pages: 7947-7957
  • Peer Reviewed
• [Journal Article] Unconventional splicing of XBP1 mRNA occurs in the cytoplasm during mammalian unfolded protein response (2009)
  • Author(s): A. Uemura, M. Oku, K. Mori, and H. Yoshida
  • Journal Title: J. Cell Sci. Volume: 122 Issue: 16 Pages: 2877-2886
  • DOI: 10.1242/jcs.040584
  • Peer Reviewed
• [Journal Article] Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow (2009)
  • Author(s): L. Zeng, A. Zampetaki, A. Margariti, A. E. Pepe, S. Alam, D. Martin, Q. Xiao, W. Wang, Z. Jin, G. Cockerill, K. Mori, Y. J. Li, Y. Hu, S. Chien and Q. Xu
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 106 Issue: 20 Pages: 8326-8331
  • DOI: 10.1073/pnas.0903197106
  • Peer Reviewed
• [Journal Article] pXBP1(U), a Negative Regulator of the Unfolded Protein Response Activator pXBP1(S), Targets ATF6 but not ATF4 in Proteasome-mediated Degradation (2009)
  • Author(s): H. Yoshida, A. Uemura and K. Mori
  • Journal Title: Cell Structure and Function Volume: 34 Issue: 1 Pages: 1-10
  • DOI: 10.1247/csf.06028
  • NAID: 130004137539
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed
• [Journal Article] Unconventional splicing of XBP1 mRNA occurs in the cytoplasm during mammalian unfolded protein response. (2009)
  • Author(s): A. Uemura, M. Oku, K. Mori, H. Yoshida
  • Journal Title: J. Cell Sci. 122 Pages: 2877-2886
  • Peer Reviewed
• [Journal Article] Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow. L. Zeng (2009)
  • Author(s): A. Zampetaki, A. Margariti, A.E. Pepe, S. Alam, D. Martin, Q. Xiao, W. Wang, Z. Jin, G. Cockerill, K. Mori, Y.J. Li, Y. Hu, S. Chien, Q. Xu
  • Journal Title: Proc. Natl. Acad. Sci. USA 106 Pages: 8326-8331
  • Peer Reviewed
• [Journal Article] p31 deficiency influences endoplasmic reticulum tubular morphology and cell survival. (2009)
  • Author(s): T. Uemura, T. Sato, T. Aoki, A. Yamamoto, T. Okada, R. Hirai, R. Harada, K. Mori, M. Tagaya, A. Harada
  • Journal Title: Mol. Cell. Biol. 29 Pages: 1869-1881
  • NAID: 120004898418
  • Peer Reviewed
• [Journal Article] pXBP1(U), a negative regulator of the unfolded protein response activator pXBP1(S), targets ATF6 but not ATF4 in proteasome-mediated degradation. (2009)
  • Author(s): H. Yoshida, A. Uemura, K. Mori
  • Journal Title: Cell Struc. Func 34 Pages: 1-10
  • NAID: 130004137539
  • Peer Reviewed
• [Journal Article] Sustained activation of XBP1 splicing leads to endothelial apoptosis and atherosclerosis development in response to disturbed flow. (2009)
  • Author(s): L.Zeng, A.Zampetaki, A.Margariti, A.E.Pepe, S.Alam, D.Martin, Q.Xiao, W.Wang, Z.Jin, G.Cockerill, K.Mori, Y.J.Li, Y.Hu, S.Chien, Q.Xu
  • Journal Title: Proc.Natl.Acad.Sci. USA 106 Pages: 8326-8331
  • Peer Reviewed
• [Journal Article] Unconventional splicing of XBPl mRNA occurs in the cytoplasm during mammalian unfolded protein response. (2009)
  • Author(s): A.Uemura, M.Oku, K.Mori, H.Yoshida
  • Journal Title: J.Cell Sci. 122 Pages: 2877-2886
  • Peer Reviewed
• [Journal Article] pXBP1(U), a negative regulator of the unfolded protein response activator pXBP1(S), targets ATF6 but not ATF4 in proteasome-mediated degradation (2009)
  • Author(s): H. Yoshida, A. Uemura and K. Mori
  • Journal Title: Cell Struc. Func 34 Pages: 1-10
  • NAID: 130004137539
  • Peer Reviewed
• [Journal Article] p31 deficiency influences endoplasmic reticulum tubular morphology and cell survival (2009)
  • Author(s): T. Uemura, T. Sato, T. Aoki, A. Yamamoto, T. Okada, R. Hirai, R. Harada, K. Mori, M. Tagaya, and A. Harada
  • Journal Title: Mol. Cell. Biol 29 Pages: 1869-1881
  • NAID: 120004898418
  • Peer Reviewed
• [Journal Article] Human HRD1 promoter carries a functional unfolded protein response element to which XBP1 but not ATF6 directly binds (2008)
  • Author(s): K. Yamamoto, N. Suzuki, T. Wada, T. Okada, H. Yoshida, R. J. Kaufman and K. Mori
  • Journal Title: J. Biochem. Volume: 144 Issue: 4 Pages: 477-486
  • DOI: 10.1093/jb/mvn091
  • NAID: 10024912784
  • Peer Reviewed
• [Journal Article] ATF6 Is a Transcription Factor Specializing in the Regulation of Quality Control Proteins in the Endoplasmic Reticulum (2008)
  • Author(s): Y. Adachi, K. Yamamoto, T. Okada, H. Yoshida, A. Harada and K. Mori
  • Journal Title: Cell Structure and Function Volume: 33 Issue: 1 Pages: 75-89
  • DOI: 10.1247/csf.07044
  • NAID: 130004137529
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed
• [Journal Article] Human HRD1 promoter carries a functional unfolded protein response element to which XBP1 but not ATF6 directly binds. (2008)
  • Author(s): K. Yamamoto, N. Suzuki, T. Wada, T. Okada, H. Yoshida, R.J. Kaufman, K. Mori
  • Journal Title: J. Biochem. 144 Pages: 477-486
  • NAID: 10024912784
  • Peer Reviewed
• [Journal Article] Human HRD1 promoter carries a functional unfolded protein response element to which XBP1 but not ATF6 directly binds (2008)
  • Author(s): K. Yamamoto, N. Suzuki, T. Wada, T. Okada, H. Yoshida, R. J. Kaufman and K. Mori
  • Journal Title: J. Biochem 144 Pages: 477-486
  • NAID: 10024912784
  • Peer Reviewed
• [Journal Article] Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6α and XBP1 (2007)
  • Author(s): K. Yamamoto, T. Sato, T. Matsui, M. Sato, T. Okada, H. Yoshida, A. Harada and K. Mori
  • Journal Title: Dev. Cell Volume: 13 Issue: 3 Pages: 365-376
  • DOI: 10.1016/j.devcel.2007.07.018
  • Peer Reviewed
• [Journal Article] Role of disulfide bridges formed in the luminal domain of ATF6 in sensing endoplasmic reticulum stress (2007)
  • Author(s): S. Nadanaka, T. Okada, H. Yoshida, and K. Mori
  • Journal Title: Mol. Cell. Biol. Volume: 27 Issue: 3 Pages: 1027-1043
  • DOI: 10.1128/mcb.00408-06
  • Peer Reviewed
• [Presentation] The forefront of endoplasmic reticulum stress research (2012)
  • Author(s): 森和俊
  • Organizer: 第85回日本薬理学会年会シンポジウムム『創薬のターゲットとしての小胞体ストレス』
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2012-03-16
• [Presentation] 小胞体ストレス応答によるタンパク質品質管理 (2011)
  • Author(s): 森和俊
  • Organizer: 第84回日本生化学会大会特別講演
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2011-09-23
• [Presentation] 小胞体ストレス応答によるタンパク質品質管理 (2011)
  • Author(s): 森和俊
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 国立京都国際会館(京都府)(招待講演)
  • Year and Date: 2011-09-23
• [Presentation] 小胞体ストレス応答によるタンパク質品質管理 (2011)
  • Author(s): 森和俊
  • Organizer: 第54回日本糖尿病学会年次学術集会特別講演
  • Place of Presentation: さっぽろ芸術文化の館
  • Year and Date: 2011-05-21
• [Presentation] 小胞体ストレスと病気 (2011)
  • Author(s): 森和俊
  • Organizer: 第27回日本毒性病理学会学術集会特別講演
  • Place of Presentation: 大阪国際交流センター
  • Year and Date: 2011-01-27
• [Presentation] The Unfolded Protein Response in Oryzias latipes (2010)
  • Author(s): 森和俊
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会・合同大会ワークショップ『種々のモデル生物を用いた小胞体ストレス研究の最前線』
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2010-12-08
• [Presentation] メダカにおける小胞体ストレス応答 (2010)
  • Author(s): 森和俊
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会・合同大会
  • Place of Presentation: 神戸国際会議場(招待講演)
  • Year and Date: 2010-12-08
• [Presentation] メダカ小胞体ストレス応答の解析 (2009)
  • Author(s): 石川時郎, 岡田徹也, 谷口善仁, 武田俊一, 森和俊
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2009-10-22
• [Presentation] メダカ小胞体ストレス応答の解析 (2009)
  • Author(s): 石川時郎, 岡田徹也, 谷口善仁, 武田俊一, 森和俊
  • Organizer: 第82回日本生化学会大会.
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2009-10-22
• [Presentation] 小胞体関連分解タンパク質Derlins結合タンパク質の同定と解析 (2008)
  • Author(s): 蜷川暁、岡田徹也、小田裕香子、大川克也、森和俊
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会合同大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2008-12-09
• [Presentation] 小胞体関連分解タンパク質Derlins結合タンパク質の同定と解析 (2008)
  • Author(s): 蜷川暁、岡田徹也、小田裕香子、大川克也、森和俊
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会合同大会
  • Place of Presentation: 神戸市
• [Presentation] ATF6は小胞体におけるタンパク質の品質管理に必須な普遍的膜結合性転写因子である (2007)
  • Author(s): 森和俊
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会・合同大会)シンポジウム『メンブレントラフィックとオルガネラの機能』演題
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-12-13
• [Remarks]
  • URL: http://www.upr.biophys.kyoto-u.ac.jp/
• [Remarks]
  • URL: http://www.upr.biophys.kyoto-u.ac.jp/
• [Remarks]
  • URL: http://www.upr.biophys.kyoto-u.ac.jp/