Dysregulation of Sulfated Glycosaminoglycan Biosynthesis is Implicated in Inflammatory Response

• Project/Area Number: 25460080
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Kobe Pharmaceutical University
• Principal Investigator: Nadanaka Satomi 神戸薬科大学, 薬学部, 講師 (60378578)
• Co-Investigator(Renkei-kenkyūsha): Kitagawa Hiroyuki 神戸薬科大学, 薬学部, 教授 (40221915)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: proteoglycan / glycosaminoglycan / 糖鎖生物学 / プロテオグリカン / グリコサミノグリカン / コンドロイチン硫酸 / 炎症

Outline of Final Research Achievements

GAGs (glycosaminoglycans) are abundant on the surfaces of most cells and in extracellular matrices as components of PGs (proteoglycans). PGs play important roles in homoeostasis at the cellular and tissue level because they function as cofactors in a variety of biological processes, including cell growth, and cell differentiation. These functions of PGs are mediated by interactions between GAG chains and bioactive proteins. In addition, diverse protein ligands recognize the specific saccharide sequences of the GAG side chains. Thus abnormal GAG biosynthesis causes disordered cellular function and various disease conditions. EXTL2 (exostosin-like 2) is one of a regulator to regulate in vivo GAG biosynthesis. Thus, loss of EXTL2 causes a change in amount and structure of GAGs, and the resulting aberrant GAGs are linked to pathological conditions. In this study, we have demonstrated that abnormal GAGs produced in the absence of EXTL2 induce inflammatory response and how they do so.

Research Products

• [Journal Article] Structural Requirements of Glycosaminoglycans for Facilitating Amyloid Fibril Formation of Human Serum Amyloid A (2016)
  • Author(s): Takase H., Tanaka M., Yamamoto A., Watanabe S., Takahashi S., Nadanaka S., Kitagawa H., Yamada T., Mukai T.
  • Journal Title: Amyloid Volume: 印刷中 Issue: 2 Pages: 67-75
  • DOI: 10.3109/13506129.2016.1168292
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] TFE3 Is a bHLH-ZIP-type Transcription Factor that Regulates the Mammalian Golgi Stress Response (2015)
  • Author(s): Taniguchi, M., Nadanaka, S., Tanakura, S., Sawaguchi, S., Midori, S., Kawai, Y., Yamaguchi, S., Shimada, Y., Nakamura, Y., Matsumura, Y., Fujita, N., Araki, N., Yamamoto, M., Oku, M., Wakabayashi, S., Kitagawa, H., Yoshida, H.
  • Journal Title: Cell Structure and Function Volume: 40 Issue: 1 Pages: 13-30
  • DOI: 10.1247/csf.14015
  • NAID: 130004703720
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] EXTL2 controls liver regeneration and aortic calcification through xylose kinase-dependent regulation of glycosaminoglycan biosynthesis. (2014)
  • Author(s): Nadanaka, S., and Kitagawa, H.
  • Journal Title: Matrix Biol. Volume: 35 Pages: 18-24
  • DOI: 10.1016/j.matbio.2013.10.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Heparan sulfate containing unsubstituted glucosamine residues: biosynthesis and heparanase inhibitory activity. (2014)
  • Author(s): Satomi Nadanaka, Eko Purunomo, Naoko Takeda, Jun-ichi Tamura and Hirosi Kitagawa
  • Journal Title: The Journal of Biological Chemistry Volume: 289 Issue: 22 Pages: 15231-15243
  • DOI: 10.1074/jbc.m113.545343
  • Peer Reviewed / Open Access
• [Journal Article] Glycosaminoglycan Overproduction in the Aorta Increases Aortic Calcification in Murine Chronic Kidney Disease. (2013)
  • Author(s): Purnomo E, Emoto N, Nugrahaningsih DAA, Nakayama K, Yagi K, Heiden S, Nadanaka S, Kitagawa H, Hirata KI.
  • Journal Title: JAHA Volume: 2 Issue: 5
  • DOI: 10.1161/jaha.113.000405
  • Peer Reviewed
• [Journal Article] The antipsychotic olanzapine induces apoptosis in insulin-secreting pancreatic β cells by blocking PERK-mediated translational attenuation. (2013)
  • Author(s): Ozasa, R., Okada, T., Nadanaka, S., Nagamine, T., Zyryanova, A., Harding, H., Ron, D., and Mori, K.
  • Journal Title: Cell Struct. Funct. Volume: 38 Pages: 183-183
  • NAID: 130004137596
  • Peer Reviewed
• [Journal Article] Roles of EXTL2, a member of EXT family of tumor suppressors, in liver injury and regeneration processes. (2013)
  • Author(s): Nadanaka, S., Kagiyama, S., and Kitagawa, H.
  • Journal Title: Biochem. J. Volume: 454 Issue: 1 Pages: 133-145
  • DOI: 10.1042/bj20130323
  • Peer Reviewed
• [Journal Article] EXTL2, a member of the EXT family of tumor suppressors, controls glycosaminoglycan biosynthesis in a xylose kinase-dependent manner. (2013)
  • Author(s): Nadanaka, S., Zhou, S., Kagiyama, S., Shoji, N., Sugahara, K., Sugihara, K., Asano, M., and Kitagawa, H.
  • Journal Title: J. Biol. Chem. Volume: 288 Pages: 9321-9321
  • Peer Reviewed
• [Presentation] Dysregulated GAG Biosynthesis Affects Inhibitory Interneuron Proliferation During Neural Development and Causes Behavioral Disorders (2016)
  • Author(s): Satomi Nadanaka, Aya Ikeda, Atsushige Ishino, Koichi Onoi, Hiroshi Kitagawa
  • Organizer: The 3rd International Symposium on Glyco-Neuroscience
  • Place of Presentation: Awaji Yumebutai International Conference Center (Hyogo)
  • Year and Date: 2016-01-14
  • Int'l Joint Research
• [Presentation] 神経細胞の分化過程におけるコンドロイチン硫酸の合成制御機構 (2015)
  • Author(s): 灘中 里美, 山田 英美, 中村 侑, 谷口 麻衣, 吉田 秀郎, 北川 裕之
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートビアアイランド（兵庫）
  • Year and Date: 2015-12-01
• [Presentation] 神経細胞の分化過程におけるコンドロイチン硫酸の合成制御機構 (2015)
  • Author(s): 灘中 里美, 山田 英美, 中村 侑, 谷口 麻衣, 吉田 秀郎, 北川 裕之
  • Organizer: 平成27年度神経糖鎖生物学夏の班会議（第９回非公開班会議プログラム）
  • Place of Presentation: とりぎん文化会館（鳥取）
  • Year and Date: 2015-06-25
• [Presentation] ヘパラン硫酸の合成異常が神経発生と行動に与える影響についての解析 (2015)
  • Author(s): 池田 亜弥，石野 敦重, 尾ノ井 孝一, 中村 侑, 灘中 里美, 北川 裕之
  • Organizer: 第62回日本生化学会近畿支部例会（立命館大学びわこ・くさつキャンパス）
  • Place of Presentation: 立命館大学びわこ・くさつキャンパス（滋賀）
  • Year and Date: 2015-05-16
• [Presentation] ヘパラン硫酸の合成異常が神経発生と行動に与える影響についての解析 (2015)
  • Author(s): 池田 亜弥，○石野 敦重, 尾ノ井 孝一, 中村 侑, 灘中 里美, 北川 裕之
  • Organizer: 第６２回日本生化学会近畿支部
  • Place of Presentation: 立命館大学 びわこ・くさつキャンパス
  • Year and Date: 2015-05-16
• [Presentation] Heparan Sulfate Containing Unsubstituted Glucosamine Residues: Biosynthesis and Heparanase Inhibitory Activity (2014)
  • Author(s): Satomi Nadanaka, Eko Purunomo, Naoko Takeda, Jun-ichi Tamura, and Hiroshi Kitagawa
  • Organizer: SFG JSCR Joint Meetin
  • Place of Presentation: Hawaii
  • Year and Date: 2014-11-16 – 2014-11-19
• [Presentation] Dysregulated GAG Biosynthesis Affects Inhibitory Interneuron Proliferation During Neural Development and Causes Behavioral Disorders (2014)
  • Author(s): Satomi Nadanaka, and Hiroshi Kitagawa
  • Organizer: SFG JSCR Joint Meetin Sattelite II
  • Place of Presentation: Hawaii
  • Year and Date: 2014-11-16 – 2014-11-19
• [Presentation] 遊離グルコサミン残基を含むヘパラン硫酸 ーその生合成機構とヘパラナーゼ阻害活性ー (2014)
  • Author(s): 灘中里美、Eko Purunomo、武田尚子、田村純 一、北川 裕之
  • Organizer: 第３３回 日本糖質学会年会
  • Place of Presentation: 名古屋大学 豊田講堂
  • Year and Date: 2014-08-10 – 2014-08-12
• [Presentation] EXTL2 によるグリコサミノグリカン合成調節機構とその破綻による急性肝炎の重篤化 (2013)
  • Author(s): 灘中里美, Shaobo Zhou, 鍵山正二, 庄司奈緒子, 菅原一幸, 杉浦一司, 浅野雅秀, 北川裕之
  • Organizer: 第３２回日本糖質学会年会
  • Place of Presentation: 大阪
• [Book] 糖鎖の新機能開発・応用ハンドブック 創薬・医療から食品開発まで (2015)
  • Author(s): 監修 秋吉一成, 編集委員 津本浩平, 編集員 加藤晃一 鷲羽武史 深瀬浩一 古川鋼一, （p. 36-40 著者:灘中里美, 北川裕之）
  • Total Pages: 678
  • Publisher: 株式会社 エヌ・ティー・エス NTS
• [Book] andbook of Glycosyltransferases and Related Genes, 2nd Ed (Taniguchi, N., Honke, K., Fukuda, M., Narimatsu, H., Yamaguchi, Y., and Angata, T., eds) (2014)
  • Author(s): Nadanaka, S., and Kitagawa, H.
  • Publisher: Springer
• [Book] Handbook of Glycosyltransferases and Related Genes (2014)
  • Author(s): Nadanaka, S., and Kitagawa, H.
  • Publisher: Springer
• [Remarks] 神戸薬科大学生化学研究室オリジナルホームページ
  • URL: http://www.kobepharma-u.ac.jp/biochem/
• [Remarks] 神戸薬科大学ホームページ教員・研究室紹介 生化学研究室
  • URL: http://www.kobepharma-u.ac.jp/edrs/faculty_member_list/biochemistry.html
• [Remarks] 生化学研究室 教育・研究 神戸薬科大学
  • URL: http://www.kobepharma-u.ac.jp/edrs/faculty_member_list/biochemistry.html
• [Remarks] 神戸薬科大学生化学研究室ホームページ
  • URL: http://www.kobepharma-u.ac.jp/rsch/rsch_03.html