Analyses of the physiological roles of unfolded protein response

2012 Fiscal Year Final Research Report

• Project Area: Protein community: organization and maintenance of protein functions
• Project/Area Number: 19058010
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Nara Institute of Science and Technology
• Principal Investigator: KOHNO Kenji 奈良先端科学技術大学院大学, バイオサイエンス研究科, 教授 (50142005)
• Co-Investigator(Kenkyū-buntansha): TSURU Akio 奈良先端科学技術大学院大学, バイオサイエンス研究科, 助教 (80273861) ; TERADA Kazutoyo 熊本大学, 大学院・生命科学研究部, 准教授 (00253724)
• Research Collaborator: KIMATA Yukio 奈良先端科学技術大学院大学, バイオサイエンス研究科, 准教授 (60263448) ; YANAGITANI Kota 奈良先端科学技術大学院大学, バイオサイエンス研究科, 特任助教 (70614775) ; SAITO Michiko 奈良先端科学技術大学院大学, バイオサイエンス研究科, 助教 (40379558) ; KADOKURA Hiroshi 奈良先端科学技術大学院大学, バイオサイエンス研究科, 博士研究員 (70224558) ; YAMAMOTO Yohei 奈良先端科学技術大学院大学, バイオサイエンス研究科, 博士研究員
• Project Period (FY): 2007 – 2012
• Keywords: 小胞体ストレス / タンパク質品質管理 / シグナル伝達 / 転写翻訳調節 / Hsp40

Research Abstract

Activation process of ER stress sensor IRE1, which is an evolutionary highly conserved protein, has been studied. When misfolded and unfolded proteins accumulated in the ER by some various stresses, IRE1 sensors formed clusters and directly interacted with unfolded protein, resulting in the full activation of IRE1. Activated IRE1 attenuated ER stress by the transcriptional induction of UPR target genes. This activation process has been evolutionarily conserved from yeasts to humans. Specific inactivation of IRE1α gene in murine islet β cells caused diabetes in mice, whose mechanism has been unknown. Finally we found novel molecular chaperons located in the ER membrane stimulated the degradation of misfolded membrane proteins to attenuate ER stress.

Research Products

• [Journal Article] Negative feedback by IRE1β optimizes mucin production in goblet cells (2013)
  • Author(s): Tsuru, A., Fujimoto, N., Takahashi, S.,Saito, M., Nakamura, D., Iwano, M., Iwawaki, T., Kadokura, H., Ron, D., Kohno, K
  • Journal Title: Proc Natl Acad Sci USA Volume: 110 Pages: 2864-2869
  • Peer Reviewed
• [Journal Article] A BiP-bound and non-clustered mode of Ire1 evokes a weak but sustained unfolded protein response (2013)
  • Author(s): Ishiwata-Kimata, Y., Promlek, T., Kohno, K., Kimata, Y
  • Journal Title: Genes Cells Volume: 18 Pages: 288-301
  • Peer Reviewed
• [Journal Article] A novel mammalian ER-located J-protein, DNAJB14, can accelerate ERAD of misfolded membrane proteins (2012)
  • Author(s): Sopha, P., Kadokura, H., Yamamoto, Y.H., Takeuchi, M., Saito, M., Tsuru, A., Kohno, K
  • Journal Title: Cell Struct. Funct Volume: 37 Pages: 177-187
  • Peer Reviewed
• [Journal Article] Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum-stress sensor Ire1 by different manners (2011)
  • Author(s): Promlek, T., Ishiwata-Kimata, Y., Shido, M., Sakuramoto, M., Kohno, K. Kimata, Y
  • Journal Title: Mol. Biol. Cell Volume: 22 Pages: 3520-3532
  • Peer Reviewed
• [Journal Article] Reconstitution and characterization of the unconventional slicing of XBP1u mRNA in vitro (2011)
  • Author(s): Shinya, S., Kadokura, H., Imagawa, Y., Inoue, M., Yanagitani, K., and Kohno, K
  • Journal Title: Nucleic Acids Res Volume: 39 Pages: 5245-5254
  • Peer Reviewed
• [Journal Article] Optimal functional levels ofactivation-induced deaminase specificallyrequire the Hsp40 DnaJa1 (2011)
  • Author(s): Orthwein, A., Zahn, A., Methot, S.P., Godin, D., Conticello, S.G., Terada, K., Noia, J.M
  • Journal Title: EMBO J Volume: 31 Pages: 679-691
  • Peer Reviewed
• [Journal Article] Translational pausing ensures membrane-targeting and cytoplasmic splicing of XBP1u mRNA (2011)
  • Author(s): Yanagitani, K., Kimata, Y., Kadokura, H., Kohno, K
  • Journal Title: Science Volume: 331 Pages: 586-589
  • Peer Reviewed
• [Journal Article] ER stress-sensing mechanisms in yeast and mammalian cells (2011)
  • Author(s): Kimata, Y., Kohno, K
  • Journal Title: Curr. Opin. Cell Biol Volume: 23 (2) Pages: 135-142
  • Peer Reviewed
• [Journal Article] Mammalian ER stress sensor IRE1β specifically down-regulates the synthesis of secretory pathway proteins (2011)
  • Author(s): Nakamura, D., Tsuru, A., Ikegami, K., Imagawa, Y., Fujimoto, N., Kohno, K.
  • Journal Title: FEBS Lett Volume: 585 Pages: 133-138
  • Peer Reviewed
• [Journal Article] A novel ER J-protein DNAJB12 accelerates ER-associated degradation of membraneproteins including CFTR (2010)
  • Author(s): Yamamoto, Y., Kimura, T., Momohara, S., Takeuchi, M., Tani, T., Kimata, Y., Kadokura, H., Kohno, K
  • Journal Title: Cell Struct. Funct Volume: 35 Pages: 107-116
  • Peer Reviewed
• [Journal Article] IRE1α disruption causes histological abnormalityof exocrine tissues, increse of blood glucoselevel, and decrease of serum immunoglobulin level (2010)
  • Author(s): Iwawaki, T., Akai, R., Kohno, K
  • Journal Title: PLoSONE Volume: 5 (9) Pages: e13052 1-11
  • Peer Reviewed
• [Journal Article] The endoplasmic reticulum stress-CHOP pathway-mediatedapoptosis in macrophages contributes to the instability of atherosclerotic plaques (2010)
  • Author(s): Tsukano, H., Gotoh, T., Endo, M., Miyata, K., Tazume, H., Kadomatsu, T.,Yano, M., Iwawaki, T., Kohno, K., Araki, K., Mizuta, H., Oike, Y
  • Journal Title: Arterioscler. Thromb. Vasc. Biol Volume: 30 Pages: 1925-1932
  • Peer Reviewed
• [Journal Article] Multiple molecules of Hsc70 and a dimer of DjA1independently bind to an unfolded protein (2010)
  • Author(s): Terada, K., Oike, Y
  • Journal Title: J. Biol. Chem Volume: 285 Pages: 16789-16797
  • Peer Reviewed
• [Journal Article] Stress sensing mechanisms in the unfolded protein response:similarities and differences between yeastand mammals (2010)
  • Author(s): Kohno, K
  • Journal Title: J. Biochem Volume: 147 Pages: 27-33
  • Peer Reviewed
• [Journal Article] Positive contribution of ERdj5/JPDI to endoplasmic reticulum protein quality control in the salivary gland (2010)
  • Author(s): Hosoda, A., Tokuda, M., Akai, R., Kohno, K., Iwawaki, T
  • Journal Title: Biochem. J Volume: 425 Pages: 117-125
  • Peer Reviewed
• [Journal Article] Pioglitazone reduces ER stress in the liver: Direct monitoring of in vivo ER stress using ER stress-activated indicator transgenic mice (2009)
  • Author(s): Yoshiuchi, K., Kaneto, H., Matsuoka, TA, Kasami, R., Kohno, K., Iwawaki, T., Nakatani, Y., Yamasaki, Y., Shimomura, I., Matsuhisa, M
  • Journal Title: Endocr. J Volume: 56 Pages: 1103-1111
  • Peer Reviewed
• [Journal Article] Function of IRE1alpha in the placenta is essential for placental development and embryonic viability (2009)
  • Author(s): Iwawaki, T., Akai, R., Yamanaka, S., Kohno, K
  • Journal Title: Proc Natl Acad Sci USA Volume: 106 Pages: 16657-16662
  • Peer Reviewed
• [Journal Article] Activation of mammalian IRE1a upon ER stress depends on dissociation of BiP rather than on direct interaction with unfolded proteins (2009)
  • Author(s): Oikawa, D., Kimata Y, Kohno, K., Iwawaki, T
  • Journal Title: Exp.Cell Res Volume: 315 Pages: 2496-2504
  • Peer Reviewed
• [Journal Article] Cotranslational targeting ofXBP1 protein to the membrane promotescytoplasmic splicing of its own mRNA (2009)
  • Author(s): Yanagitani, K., Imagawa, Y., Iwawaki,T., Hosoda, A., Saito, M., Kimata, Y., and Kohno, K
  • Journal Title: Mol. Cell Volume: 34 Pages: 191-200
  • Peer Reviewed
• [Journal Article] ALS-linked P56S-VAPB, an aggregated loss-of-function mutant of VAPB, predisposes motor neurons to ER stress-induced death by inducing aggregation of co-expressed wild-type VAPB (2009)
  • Author(s): Suzuki, H., Kanekura, K., Levine, T., Kohno, K., Olkkonen, V.M., Aiso, S., Matsuoka M
  • Journal Title: J. Neurochem Volume: 108 Pages: 973-985
  • Peer Reviewed
• [Journal Article] Sacchromyces cerevisiae Rot1 functions as a molecular chaperone in the endoplasmic reticulum (2008)
  • Author(s): Takeuchi, M., Kimata Y., Kohno, K
  • Journal Title: Mol. Biol. Cell Volume: 19 Pages: 3514-3525
  • Peer Reviewed
• [Journal Article] RNase domains determine the functional difference between IRE1a and IRE1b (2008)
  • Author(s): Imagawa, Y., Hosoda, A., Sasaka, S.,Tsuru, A., Kohno, K
  • Journal Title: FEBS Lett Volume: 582 Pages: 656-660
  • Peer Reviewed
• [Journal Article] Direct monitoring of in vivo ER stress during thedevelopment of insulin resistance with ER stress-activated indicator transgenic mice (2008)
  • Author(s): Yoshiuchi K, Kaneto H, Matsuoka TA, Kohno, K., Iwawaki T, Nakatani Y, Yamasaki Y, Hori M, Matsuhisa M
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 366 Pages: 545-550
  • Peer Reviewed
• [Journal Article] How transmembrane proteins sense endoplasmic reticulum stress (2007)
  • Author(s): Kohno, K
  • Journal Title: Antioxid. Redox Signal Volume: 9 Pages: 2295-2303
  • Peer Reviewed
• [Journal Article] Recent advances in understanding the unfoldedprotein response (2007)
  • Author(s): Schroder, M., Kohno, K
  • Journal Title: Antioxid. Redox Signal Volume: 9 Pages: 2241-2244
  • Peer Reviewed
• [Journal Article] Two regulatory steps of ER-stress sensor Ire1 involving its clusterformation and binding to unfolded proteins (2007)
  • Author(s): Kimata, Y., Ito, T., Ishiwata-Kimata, Y., Suzuki, T., Oikawa, D., Takeuchi, M., Kohno, K
  • Journal Title: J. Cell Biol Volume: 179 Pages: 75-86
  • Peer Reviewed
• [Journal Article] Transgenic mice expressing a fully nontoxic diphtheria toxin mutant, not CRM197 mutant, acquire immune tolerance against diphtheria toxin (2007)
  • Author(s): Kimura, Y., Saito, M., Kimata, Y. Kohno, K
  • Journal Title: J. Biochem Volume: 142 Pages: 105-112
  • Peer Reviewed
• [Presentation] Physiological roles of mammalian ER stress sensors, IRE1α and IRE1β (2012)
  • Author(s): 河野憲二
  • Organizer: 第85回日本生化学会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-16
• [Presentation] 哺乳動物細胞小胞体内におけるジスルフィド結合形成能力の低下を検出する為の鋭敏なアッセイ系の構築 (2012)
  • Author(s): 門倉広,河野憲二
  • Organizer: 第85回日本生化学会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-16
• [Presentation] "Ribosomal stalling promotes XBP1u mRNA splicing upon ER stress." EMBO conference (2012)
  • Author(s): Yanagitani Kota, Kohno Kenji
  • Organizer: "The Physiology of the endoplasmic reticulum (ER): Function & Dysfunction"Girona
  • Place of Presentation: Spain
  • Year and Date: 2012-10-17
• [Presentation] 生物のストレス解消システムとその破綻による疾患 (2012)
  • Author(s): 河野憲二
  • Organizer: 2012年度日本農芸化学会関西支部大会
  • Place of Presentation: 亀岡
  • Year and Date: 2012-09-07
• [Presentation] Ribosome pausing promotes XBP1 mRNA unconventional splicing upon ER stress (2012)
  • Author(s): Kohno Kenji
  • Organizer: 第12回日本蛋白質科学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2012-06-22
• [Presentation] Membrane aberrancy and unfolded proteins activate the endoplasmic reticulum-stress sensor Ire1 by different manners (2012)
  • Author(s): Yuki Kimata-Ishiwata, Kenji Kohno, Yukio Kimata
  • Organizer: 第45回日本発生生物学会・第64回日本細胞生物学会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2012-05-30
• [Presentation] Negative feedback by IRE1β optimizes mucin production in goblet cells (2012)
  • Author(s): Akio Tsuru, Michiko Saito, Megumi Iwano, Takao Iwawaki, David Ron, Kenji Kohno
  • Organizer: Cold Spring Harbor Meeting: Molecular Chaperones and Stress Response
  • Place of Presentation: Cold Spring Harbor, USA
  • Year and Date: 2012-05-04
• [Presentation] IRE1β, not IRE1α, is a key molecule for ER quality control in goblet cells (2011)
  • Author(s): Kenji Kohno
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-15
• [Presentation] Ribosomal stalling promotes mRNA splicing on the endoplasmic reticulum (2011)
  • Author(s): Kota Yanagitani, Yukiko Yokota, Yukio Kimata, Hiroshi Kadokura, Kenji Kohno
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-15
• [Presentation] 小胞体ストレス応答の分子機構と生理的役割 (2011)
  • Author(s): 河野憲二
  • Organizer: 第19回日本胎盤学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2011-09-30
• [Presentation] A novel translational regulation in the unfolded protein response (2011)
  • Author(s): Kota Yanagitani, Kenji Kohno
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-23
• [Presentation] IRE1β, not IRE1α, is a key molecule for ER quality control in goblet cells (2011)
  • Author(s): Kenji Kohno
  • Organizer: Cold Spring Harbor Conferences Asia
  • Place of Presentation: Suzhou, China
  • Year and Date: 2011-09-21
• [Presentation] "A novel translational regulation in the unfolded protein response" "A novel translational regulation in the unfolded protein response" (2011)
  • Author(s): Kenji Kohno
  • Organizer: Gordon Research Conferences "Stress Proteins in Growth, Development & Disease"
  • Place of Presentation: Lucca, Italy
  • Year and Date: 2011-07-19
• [Presentation] Translational pausing in mammalian unfolded protein response (2010)
  • Author(s): Kenji Kohno
  • Organizer: The 3rd International Symposium "Protein Community"
  • Place of Presentation: Nara
  • Year and Date: 2010-09-11
• [Presentation] A novel function of XBP1u protein in the unfolded protein response: the role of XBP1u in tethering of mRNA to the ER membrane (2010)
  • Author(s): Kenji Kohno
  • Organizer: Cold Spring Harbor Laboratory Meeting, Molecular Chaperones & Stress Response
  • Place of Presentation: Cold Spring Harbor, NY, USA
  • Year and Date: 2010-05-05
• [Presentation] IRE1β is a key molecule for ER quality control in goblet cells (2009)
  • Author(s): Kenji Kohno
  • Organizer: The 4th International Congress on Stress Responses in Biology and Medicine
  • Place of Presentation: Sapporo
  • Year and Date: 2009-10-07
• [Presentation] The role of IRE1 in unfolded protein response (2009)
  • Author(s): Yukio Kimata, Masato Takeuchi, Kenji Kohno
  • Organizer: IV International Conference on Molecular Mechanisms of Fungal Cell Wall Biogenesis
  • Place of Presentation: Warsaw, Poland
  • Year and Date: 2009-08-31
• [Presentation] Dynamic regulation of XBP1 mRNA distribution in the ER stress response (2009)
  • Author(s): Kenji Kohno
  • Organizer: Gordon Research Conferences: Stress Proteins in Growth, Development & Desease
  • Place of Presentation: Andover, USA
  • Year and Date: 2009-07-01
• [Presentation] Dynamic regulation of XBP1 mRNA distribution in the ER stress response (2009)
  • Author(s): Kota Yanagitani, Kenji Kohno
  • Organizer: 第61回日本細胞生物学会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-05-27
• [Presentation] IRE1beta is a key molecule for ER quality control in goblet cells (2008)
  • Author(s): Akio Tsuru, Kenji Kohno
  • 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
  • Year and Date: 2008-12-10
• [Book] 化学と生物, 50巻9号 (2012)
  • Author(s): 柳谷耕太,河野憲二
  • Total Pages: 633-640
  • Publisher: 日本農芸化学会
• [Book] 日本生化学会, 84巻4号 (2012)
  • Author(s): 柳谷耕太,河野憲二
  • Total Pages: 290-294
  • Publisher: 生化学
• [Book] 医学のための細胞生物学 (2009)
  • Author(s): 河野憲二
  • Total Pages: 251-260
  • Publisher: 南山堂
• [Book] 蛋白質核酸酵素, Vol.54 No16 (2009)
  • Author(s): 柳谷耕太,河野憲二
  • Total Pages: 2177-2183
  • Publisher: 共立出版
• [Book] 酵母のすべて (2007)
  • Author(s): 河野憲二
  • Total Pages: 304-310
  • Publisher: シュプリンガー・ジャパン
• [Remarks]
  • URL: http://bsw3.naist.jp/kouno/
• [Remarks] 河野研究室
  • URL: http://bsw3.naist.jp/courses/courses20 7.html
• [Remarks] 英語版
  • URL: http://bsw3.naist.jp/eng/courses/cours es207.html