遺伝性難病FAPの原因タンパク質、トランスサチレインの新たな品質管理機構

• Project Area: Protein community: organization and maintenance of protein functions
• Project/Area Number: 22020029
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kumamoto University
• Principal Investigator: 甲斐 広文 熊本大学, 大学院・生命科学研究部, 教授 (30194658)
• Project Period (FY): 2010 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥6,000,000 (Direct Cost: ¥6,000,000); Fiscal Year 2011: ¥3,000,000 (Direct Cost: ¥3,000,000); Fiscal Year 2010: ¥3,000,000 (Direct Cost: ¥3,000,000)
• Keywords: transthyretin / FAP / 小胞体 / derlin / HRD / ERAD

Research Abstract

本研究は、遺伝性難病である家族性アミロイドポリニューロパチー(FAP)の原因タンパク質,トランスサイレチン(TTR)の細胞内レベルでの制御機構を解明し,最終的には新規FAP治療法開発を目指し研究を実施してきた。今年度のひとつ目の課題は、変異TTRへのN型糖鎖修飾機構の分子機構の解明である。TTRの糖鎖修飾部位が立体構造内部に存在することからミスフォールディングとの関連に着目し検討を行った.その結果、小胞体局在化した変異TTR(本来,非糖鎖付加タンパク質)はミスフォールド状態に応じて,極めて稀な翻訳後N型糖鎖修飾を受けること、変異TTRへのN型糖鎖修飾は凝集性の高いTTRの可溶性維持に寄与し,ERAD経路とは異なるN型糖鎖依存的なERAD経路での分解を誘導すること、この新たな分解経路が機能しなくなると、細胞増殖スピードが低下してくること等を明らかにし、Molecular Cellに論文が受理された.本研究は、ミスフォールド状態のタンパク質の新たな分解経路の発見という極めて重要な知見を得ることができ、これらの成果は、様々な病態の発症のメカニズムに重要な視点を与えうるものである.FAPは発症まで約20-30年という比較的長い時間を必要とすることから,発症していない遺伝子保因者への治療がFAP発症抑制・遅延に非常に重要であるため,予防薬および治療薬の開発が強く望まれている.本研究知見は、我々が提案する新規治療標的である小胞体品質管理機構を利用した、変異タイプに依存せず,変異TTRの産生を抑制する肝移植と同等の治療効果が得られると期待される「変異TTRの細胞外分泌抑制・細胞内クリアランスの促進」プロジェクトにおいても有用な基礎的情報を提供した.

Research Products

• [Journal Article] Diethyldithiocarbamate induces apoptosis in HHV-8-infected primary effusion lymphoma cells via inhibition of the NF-κB pathway (2012)
  • Author(s): Matsuno T, Kariya R, Yano S, Morino-Koga S, Taura M, Suico MA, Shimauchi Y, Matsuyama S, Okamoto Y, Shuto T, Kai H, Okada S
  • Journal Title: Int J Oncol Volume: 40(4) Pages: 1071-1078
  • Peer Reviewed
• [Journal Article] Synergism Between Interleukin (IL)-17 and Toll-like Receptor 2 and 4 Signals to Induce IL-8 Expression in Cystic Fibrosis Airway Epithelial Cells (2012)
  • Author(s): Mizunoe S, Shuto T, Suzuki S, Matsumoto C, Watanabe K, Ueno-Shuto K, Suico MA, Onuki K, Gruenert DC, Kai H
  • Journal Title: J Pharmacol Sci Volume: (印刷中)
  • NAID: 10030572169
  • Peer Reviewed
• [Journal Article] Hyperthermia With Mild Electrical Stimulation Protects Pancreatic β-Cells From Cell Stresses and Apoptosis (2012)
  • Author(s): Kondo T, Sasaki K, Matsuyama R, Morino-Koga S, Adachi H, Suico MA, Kawashima J, Motoshima H, Furukawa N, Kai H, Araki E
  • Journal Title: Diabetes Volume: 61(4) Pages: 838-847
  • NAID: 120005368280
  • Peer Reviewed
• [Journal Article] Rb/E2F1 Regulates the Innate Immune Receptor Toll-Like Receptor 3 in Epithelial Cells (2012)
  • Author(s): Taura M, Suico MA, Koyama K, Komatsu K, Miyakita R, Matsumoto C, Kudo E, Kdriya R, Goto H, Kitajima S, Takahashi C, Shuto T, Nakao M, Okada S, Kai H
  • Journal Title: Mol Cell Biol Volume: 32(8) Pages: 1581-1590
  • Peer Reviewed
• [Journal Article] Lucidenic acids-rich extract from antlered form of Ganoderma lucidum enhances TNFα induction in THP-1 monocytic cells possibly via its modulation of MAP kinases p38 and JNK (2011)
  • Author(s): Watanabe K, Shuto T, Sato M, Onuki K, Mizunoe S, Suzuki S, Sato T, Koga T, Suico MA, Kai H, Ikeda T
  • Journal Title: Biochem Biophys Res Commun Volume: 408(1) Pages: 18-24
  • Peer Reviewed
• [Journal Article] CFTR-deficiency renders mice highly susceptible to cutaneous symptoms during mite infestation (2011)
  • Author(s): Hashimoto Y, Shuto T, Mizunoe S, Tomita A, Koga T, Sato T, Takeya M, Suico MA, Niibori A, Sugahara T, Shimasaki S, Sugiyama T, Scholte B, Kai H
  • Journal Title: Lab Invest Volume: 91(4) Pages: 509-518
  • Peer Reviewed
• [Journal Article] Posttranslational negative regulation of glycosylated and non-glycosylated BCRP expression by Derlin-1 (2011)
  • Author(s): Sugiyama T, Shuto T, Suzuki S, Sato T, Koga T, Suico MA, Kusuhara H, Sugiyama Y, Cyr DM, Kai H
  • Journal Title: Biochem Biophys Res Commun Volume: 404(3) Pages: 853-858
  • Peer Reviewed
• [Journal Article] Posttranslational negative regulation of glycosylated and non-glycosylated BCRP expression by Derlin-1. (2011)
  • Author(s): Sugiyama T, et al.
  • Journal Title: Biochem Biophys Res Commun. Volume: 404(3) Pages: 853-858
  • Peer Reviewed
• [Journal Article] Crystal structure of green tea polyphenol(-)-epigallocatechin gallate(EGCG)-transthyretin complex reveals novel binding site distinct fromthyroxine binding site. (2010)
  • Author(s): Miyata M, et al.
  • Journal Title: Biochemistry. Volume: 49(29) Pages: 6104-6114
  • Peer Reviewed
• [Journal Article] Role of the glutamic acid 54 residue in transthyretin stability andthyroxine binding. (2010)
  • Author(s): Miyata M, et al.
  • Journal Title: Biochemistry. Volume: 49(1) Pages: 114-123
  • Peer Reviewed
• [Presentation] アミロイド原性タンパク質の選択的分泌抑制を企図した創薬研究 (2011)
  • Author(s): 甲斐広文
  • Organizer: 第5回薬学研究フォーラムin東京～九州からの情報発信～
  • Place of Presentation: 日本薬学会長井記念館(東京)
  • Year and Date: 2011-11-14
• [Presentation] 糖鎖型および脱糖鎖型BCRPタンパク質のDerlin-1による負の翻訳後発現調節 (2011)
  • Author(s): 首藤剛, 杉山崇, 鈴木伸悟, 佐藤卓史, 古賀友紹, Mary Ann Suico, 楠原洋之, 杉山雄一, 甲斐広文
  • Organizer: 第5回トランスポーター研究会九州部会
  • Place of Presentation: ホテルJALシティ宮崎(宮崎)
  • Year and Date: 2011-09-17
• [Presentation] ABCトランスポーターABCG5およびABCG8の小胞体における翻訳後発現制御機構の解明 (2011)
  • Author(s): 鈴木伸悟, 首藤剛, 佐藤卓史, 金子雅幸, Mary Ann Suico, 甲斐広文
  • Organizer: 第5回トランスポーター研究会九州部会
  • Place of Presentation: ホテルJALシティ宮崎(宮崎)
  • Year and Date: 2011-09-17
• [Presentation] 糖鎖型および脱糖鎖型BCRPタンパク質のDerlin-1による負の翻訳後発現調節 (2011)
  • Author(s): 首藤剛, 杉山崇, 鈴木伸悟, 佐藤卓史, 古賀友紹, Mary Ann Suico, 楠原洋之, 杉山雄一, 甲斐広文
  • Organizer: 第6回トランスポーター研究会年会
  • Place of Presentation: 東北大学片平さくらホール(宮城県)
• [Presentation] 翻訳後N型糖鎖修飾によるトランスサイレチンの新規小胞体品質管理機構 (2011)
  • Author(s): 庄美里、佐藤卓史、迫康弘、桃原真美子、西頭英起、金子雅幸、メリーアン スイコ、首藤剛、甲斐広文
  • Organizer: 第28回日本薬学会九州支部大会
  • Place of Presentation: 福岡大学薬学部(福岡)
• [Presentation] 遺伝性腎疾患alport症候群に対する新たなphysical medicineの腎病態改善効果 (2011)
  • Author(s): 甲斐友佳理、古賀友紹、福田亮介、古賀(森野)沙緒里、メリーアン スイコ、小山皓介、佐藤卓史、首藤剛、甲斐広文
  • Organizer: 第28回日本薬学会九州支部大会
  • Place of Presentation: 福岡大学薬学部(福岡)
• [Presentation] HRD1-dependent endoplasmic reticulum-associated degradation pathway is involved in the clearance of transthyretin variant (2011)
  • Author(s): M.Sho, T.Sato, Y.Sako, M.Momohara, H.Nishitoh, M.Kaneko, M.A.Suico, T.Shuto, H.Kai
  • Organizer: 5th International Congress on Stress Response in Biology and Medicine
  • Place of Presentation: Loews Hotel Le Concorde, Quebec (USA)
• [Presentation] Posttranslational N-glycosylation regulates the quality control of transthyretin in the ER (2011)
  • Author(s): T.Sato, Y.Sako, M.Sho, M.Momohara, H.Nishitoh, K.Kokame, M.Kaneko, M.A.Suico, T.Shuto, T.Koga, S.Morino-Koga, I.Wada, H.Kai
  • Organizer: 8th International Symposium on Familial Amyloidotic Polyneuropathy
  • Place of Presentation: 熊本大学(熊本)
• [Presentation] Endoplasmic reticulum quality control regulates the fate of transthyretin variants in the cell (2011)
  • Author(s): T.Sato, S.Susuki, M.A.Suico, M.Miyata, Y.Ando, M.Mizuguchi, T.Shuto, H.Kai
  • Organizer: 8th International Symposium on Familial Amyloidotic Polyneuropathy
  • Place of Presentation: 熊本大学(熊本)
• [Presentation] The endoplasmic reticulum-associated degradation of transthyretin variants is negatively regulated by BiP in mammalian cells (2011)
  • Author(s): T.Sato, S.Susuki, M.Miyata, M.Momohara, M.A.Suico, T.Shuto, Y.Ando, H.Kai
  • Organizer: 8th International Symposium on Familial Amyloidotic Polyneuropathy
  • Place of Presentation: 熊本大学(熊本)
• [Presentation] Role of the glutamic acid 54 residue in transthyretin stability and thyroxine binding (2011)
  • Author(s): T.Sato, S.Susuki, M.A.Suico, M.Miyata, Y.Ando, M.Mizuguchi, T.Shuto, H.Kai
  • Organizer: 8th International Symposium on Familial Amyloidotic Polyneuropathy
  • Place of Presentation: 熊本大学(熊本)
• [Presentation] The crystal structure of the green tea polyphenol(-)-epigallocatechin gallate-transthyretin complex reveals a novel binding site distinct from the thyroxine binding site (2011)
  • Author(s): M.Sho, M.Miyata, T.Sato, T.Nakmura, S.Ikemizu, M.Chirifu, M.Mizuguchi, Y.Suwa, H.Morioka, M.A.Suico, T.Shuto, Y.Yamagata, H.Kai
  • Organizer: 8th International Symposium on Familial Amyloidotic Polyneuropathy
  • Place of Presentation: 熊本大学(熊本)
• [Presentation] Posttranslational N-glycosylation is required for the efficient ERAD of transthyretin variants. (2010)
  • Author(s): Sato T, Sako Y, Momohara M, Sho M, Nishitoh H, Kaneko M, Mary Ann Suico, Shuto T, Kai H
  • Organizer: The 3rd International Symposium on Protein Community (ISPC-Nara2010)
  • Place of Presentation: ホテル日航奈良(奈良)
• [Presentation] Posttranslational N-glycosylation is required for the efficient ERAD of transthyretin variants. (2010)
  • Author(s): Sato T, Sako Y, Momohara M, Sho M, Nishitoh H, Kaneko M, Mary Ann Suico, Shuto T, Wada I, Kai H
  • Organizer: The 50th Annual Meeting of the American Society for Cell Biology
  • Place of Presentation: Pennsylvania Convention Center(USA)
• [Presentation] Endoplasmic reticulum-associated degradation of transthyretin variant is mediated by HRD1 dependent pathway. (2010)
  • Author(s): Sako Y, Sato T, Momohara M, Sho M, Nishitoh H, Kaneko M, Mary Ann Suico, Shuto T, Kai H
  • Organizer: The 50th Annual Meeting of the American Society for Cell Biology
  • Place of Presentation: Pennsylvania Convention Center(USA)
• [Remarks]
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• [Remarks]
  • URL: http://molmed730.org/