Transglutaminase-catalyzed protein-protein crosslinking maintains the innate immunity in Drosophila

• Project/Area Number: 26860333
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Kyushu University
• Principal Investigator: Shibata Toshio 九州大学, 高等研究院, 助教 (00614257)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 腸管免疫 / 囲食膜 / トランスグルタミナーゼ / ショウジョウバエ / 外毒素プロテアーゼ / 経口感染 / タンパク質架橋 / キイロショウジョウバエ / TGase / IMD経路 / 自然免疫 / 免疫寛容 / 架橋反応 / 活性酸素

Outline of Final Research Achievements

Intestinal homeostasis is ensured by a subtle balance between bacteria and host immunity. Gut epithelial barriers, such as the mucus layer in mammals and the peritrophic matrix in invertebrates, have a protective function for hosts, as they are impermeable to the invading intestinal microbes. In this study, we discovered, in the fly Drosophila melanogaster, that transglutaminase, known to be molecular glue involved in protein-protein covalent bond formation, is essential for peritrophic matrix formation to convert a peritrophic protein Drosocrystallin into a stable fiber-like structure and to inhibit the pathogenesis against pathogenic bacteria. Knockdown of transglutaminase gene, the permeability of the peritrophic matrix was increased and the fly exhibited highly susceptibility against a bacterial toxic protease. Transglutaminase contributes to form the stable mesh-like barrier on the peritrophic matrix and tolerant for pathogenic microorganisms.

Research Products

• [Journal Article] Crosslinking of a peritrophic matrix protein protects gut epithelia from bacterial exotoxins. (2015)
  • Author(s): Shibata, T., Maki, K., Hadano, J., Fujikawa, T., Kitazaki, K., Koshiba, T., and Kawabata, S.
  • Journal Title: PLoS Pathogens Volume: 11 Issue: 10 Pages: 1-15
  • DOI: 10.1371/journal.ppat.1005244
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The N-terminal Arg residue is essential for autocatalytic activation of a lipopolysaccharide-responsive protease zymogen (2014)
  • Author(s): Kobayashi, Y., Shiga, T., Shibata, T., Sako, M., Maenaka, K., Koshiba, T., Mizumura, H., Oda, T., and Kawabata, S.
  • Journal Title: Journal of Biological Chemistry Volume: 289 Issue: 37 Pages: 25987-25995
  • DOI: 10.1074/jbc.m114.586933
  • Peer Reviewed
• [Presentation] 脂質修飾が引き起こすショウジョウバエトランスグルタミナーゼの細胞内局在性の変化 (2015)
  • Author(s): 柴田俊生、羽田野仁喜、田川圭介、川畑俊一郎
  • Organizer: BMB2015
  • Place of Presentation: 兵庫県
  • Year and Date: 2015-12-01
• [Presentation] 脂質修飾が引き起こす架橋酵素の細胞内局在性の変化 (2015)
  • Author(s): 柴田俊生、羽田野仁喜、田川圭介、川畑俊一郎
  • Organizer: 日本比較免疫学会
  • Place of Presentation: 福井県
  • Year and Date: 2015-08-21
• [Presentation] ショウジョウバエの腸内細菌に対する免疫応答と寛容の分子機構 (2015)
  • Author(s): 柴田俊生
  • Organizer: 日本炎症・再生医学会
  • Place of Presentation: 東京都
  • Year and Date: 2015-07-21
  • Invited
• [Presentation] 脂質修飾によるトランスグルタミナーゼの局在化の制御機構 (2015)
  • Author(s): 柴田俊生、羽田野仁喜、関原早苗、小柴琢己、川畑俊一郎
  • Organizer: 日本生体防御学会
  • Place of Presentation: 東京都
  • Year and Date: 2015-07-10
• [Presentation] 腸内細菌に対する免疫寛容による腸管恒常性維持 (2014)
  • Author(s): 柴田俊生、関原早苗、槇光輝、藤川匠、宮地隆太、石原健、小柴琢己、川畑俊一郎
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都市
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] ショウジョウバエの腸内細菌に対する免疫応答と寛容の分子機構 (2014)
  • Author(s): 柴田俊生、関原早苗、藤川匠、槇光輝、宮地隆太、石原健、小柴琢己、川畑俊一郎
  • Organizer: 第25回日本生体防御学会学術総会・日本比較免疫学会第26回学術集会合同学会
  • Place of Presentation: 仙台市
  • Year and Date: 2014-07-09 – 2014-07-11
• [Presentation] Transglutaminase-Catalyzed Protein-Protein Crosslinking Maintains the Gut Epithelial Immunity (2014)
  • Author(s): Toshio Shibata, Sanae Sekihara, Takumi Fujikawa, Ryuta Miyaji, Kouki Maki, Takeshi Ishihara, Takumi Koshiba, Shun-ichiro Kawabata
  • Organizer: Gordon Research Conference, Transglutaminases in Human Disease Processes
  • Place of Presentation: Lucca, Italy
  • Year and Date: 2014-06-29 – 2014-07-04
• [Presentation] ショウジョウバエ自然免疫の応答制御と腸内細菌の共生成立の分子機構 (2014)
  • Author(s): 柴田俊生、関原早苗、槇光輝、藤川匠、宮地隆太、石原健、小柴琢己、川畑俊一郎
  • Organizer: 平成26年度日本生化学会九州支部例会シンポジウム
  • Place of Presentation: 福岡市
  • Year and Date: 2014-05-17 – 2014-05-18
  • Invited
• [Book] Transglutaminases: Multiple Functional Modifiers and Targets for New Drug Discovery (2015)
  • Author(s): Toshio Shibata, Shun-ichiro Kawabata
  • Total Pages: 392
  • Publisher: Springer Japan
• [Book] Transglutaminases: Multiple functional modifiers and targets for new drug discovery (2015)
  • Author(s): Toshio Shibata, Shun-ichiro Kawabata
  • Publisher: Springer
• [Remarks] 九州大学理学研究院生物科学部門生体高分子学研究室webページ
  • URL: http://www.biology.kyushu-u.ac.jp/~biopoly/
• [Remarks] 九州大学プレスリリース
  • URL: http://www.kyushu-u.ac.jp/pressrelease/2014/2014_09_11.pdf