Elucidation of the regulatory mechanisms of ASK1 ubiquitination for developing a new treatment strategy for ASK1-related diseases

• Project/Area Number: 15K18856
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Tohoku University
• Principal Investigator: Hirata Yusuke 東北大学, 薬学研究科, 助教 (10748221)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ASK1 / Roquin-2 / TRIM48 / ユビキチン化 / TLR4 / 免疫応答

Outline of Final Research Achievements

Roquin-2 is a ubiquitin ligase that ubiquitinates a stress-responsive kinase ASK1. In this study, we identified another ubiquitination target of Roquin-2 that functions in TLR4 (the receptor for a bacterial component, LPS) signaling pathway. We found that Roquin-2 promotes ubiquitin-dependent degradation of ASK1 and the newly found target molecule, and thereby negatively regulates innate immune responses. Meanwhile, we also identified another ubiquitin ligase TRIM48 as a positive regulator of ASK1 activation. TRIM48 promotes ASK1 activation, and thus facilitates ASK1 ubiquitination mediated by Roquin-2. These findings provide comprehensive understanding of the regulatory mechanisms for ASK1 ubiqutination, which will lead to the development of novel therapeutic strategies for ASK1-related diseases.

Research Products

• [Journal Article] Trans-fatty acids promote proinflammatory signaling and cell death by stimulating the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway. (2017)
  • Author(s): Hirata, Y., Takahashi, M., Kudoh, Y., Kano, K., Kawana, H., Makide, K., Shinoda, Y., Yabuki, Y., Fukunaga, K., Aoki, J., Noguchi, T., Matsuzawa, A.
  • Journal Title: J. Biol. Chem. Volume: 印刷中 Issue: 20 Pages: 8174-8185
  • DOI: 10.1074/jbc.m116.771519
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Post-Translational Modifications of the TAK1-TAB Complex. (2017)
  • Author(s): Hirata, Y., Takahashi, M., Morishita, T., Noguchi, T., Matsuzawa, A.
  • Journal Title: Int. J. Mol. Sci. Volume: 18 Issue: 1 Pages: 205-205
  • DOI: 10.3390/ijms18010205
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Brefeldin A-inhibited guanine nucleotide-exchange factor 1 (BIG1) governs the recruitment of tumor necrosis factor receptor-associated factor 2 (TRAF2) to tumor necrosis factor receptor 1 (TNFR1) signaling complexes. (2016)
  • Author(s): Noguchi, T., Tsuchida, M., Kogue, Y., Spadini, C., Hirata, Y., Matsuzawa, A.
  • Journal Title: Int. J. Mol. Sci. Volume: 17 Issue: 11 Pages: 1869-1869
  • DOI: 10.3390/ijms17111869
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mg2+ Extrusion from Intestinal Epithelia by CNNM Proteins Is Essential for Gonadogenesis via AMPK-TORC1 Signaling in Caenorhabditis elegans. (2016)
  • Author(s): Ishii T, Funato Y, Hashizume O, Yamazaki D, Hirata Y, Nishiwaki K, Kono N, Arai H, Miki H.
  • Journal Title: PLoS Genet. Volume: 12 Issue: 8 Pages: e1006276-e1006276
  • DOI: 10.1371/journal.pgen.1006276
  • Peer Reviewed / Open Access
• [Presentation] ユビキチン化修飾を介したストレス応答キナーゼASK1の活性制御機構 (2016)
  • Author(s): 平田 祐介、工藤 勇気、森下 徹、野口 拓也、松沢 厚
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] Roquin-2によるASK1の活性制御を介した免疫応答の調節 (2016)
  • Author(s): 工藤 勇気、平田 祐介、野口 拓也、松沢 厚
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-09-25
• [Presentation] RING型ユビキチンリガーゼTRIM48によるストレス応答キナーゼASK1の活性化制御機構の解明 (2016)
  • Author(s): 森下 徹、平田 祐介、野口 拓也、松沢 厚
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-09-25
• [Presentation] Roquin-2によるASK1活性制御を介した免疫応答調節機構の解明 (2016)
  • Author(s): 平田 祐介、工藤 勇気、野口 拓也、松沢 厚
  • Organizer: 第69回酸化ストレス学会学術集会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-08-30
• [Presentation] Mechanisms of ROS-induced ASK1 activation regulated by ubiquitin-related enzymes (2016)
  • Author(s): Yusuke Hirata, Takuya Noguchi, and Atsushi Matsuzawa
  • Organizer: 第16回日本NO学会学術集会 (第9回国際NO学会)
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Roquin-2によるASK1の活性制御を介した免疫応答の調節 (2015)
  • Author(s): 工藤勇気、平田祐介、野口拓也、一條秀憲、松沢厚
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] RING型ユビキチンリガーゼTRIM48によるストレス応答キナーゼASK1の活性制御機構の解明 (2015)
  • Author(s): 森下徹、平田祐介、野口拓也、一條秀憲、松沢厚
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] Regulation of inflammatory responses through Roquin-2-mediated suppression of ASK1 activation (2015)
  • Author(s): Yuki Kudoh，Yusuke Hirata，Takuya Noguchi, and Atsushi Matsuzawa
  • Organizer: Pharmaceutical Science Symposium 2015
  • Place of Presentation: 東北大学片平さくらホール
  • Year and Date: 2015-11-16
  • Int'l Joint Research
• [Presentation] E3リガーゼTRIM48によるASK1活性化制御機構の解明 (2015)
  • Author(s): 平田祐介, 森下徹, 野口拓也, 松沢厚
  • Organizer: 第54回日本薬学会東北支部大会
  • Place of Presentation: 岩手医科大学 矢巾キャンパス
  • Year and Date: 2015-09-26
• [Presentation] ユビキチンリガーゼRoquin-2のASK1活性制御を介した免疫応答調節 (2015)
  • Author(s): 工藤 勇気，平田 祐介，野口 拓也，一條 秀憲，松沢 厚
  • 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)
  • Year and Date: 2015-09-12