Unconventional secretion mechanism of transglutaminase involving exosomes and two types of fatty acylations

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K15121
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cell biology
• Research Institution: Kyushu University
• Principal Investigator: Shibata Toshio 九州大学, 理学研究院, 助教 (00614257)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: トランスグルタミナーゼ / 脂質修飾 / エクソソーム

Outline of Final Research Achievements

Transglutaminases (TGs) play essential intracellular and extracellular roles by covalently cross-linking many proteins. Drosophila TG is encoded by one gene and has two alternative splicing-derived isoforms, TG-A and TG-B. The TGs identified to date do not have a typical signal peptide for secretion, and the molecular mechanisms of their secretion under physiologic conditions are unclear. We found that TG-A, but not TG-B, was modified concomitantly by N-myristoylation and S-palmitoylatio. Moreover, TG-A, but not TG-B, was secreted in response to a pathogenic bacteria-derived substance. Inhibitors of the conventional pathway did not suppress TG-A secretion, whereas inhibition of S-palmitoylation blocked TG-A secretion. Ultracentrifugation, electron microscopy analyses revealed that TG-A was secreted via exosome, and the secreted TG-A was taken up by other cells. In conclusion, TG-A is secreted through an unconventional pathway involving two types of fatty acylations and exosomes.

Free Research Field

生化学

Academic Significance and Societal Importance of the Research Achievements

タンパク質の脂質修飾は、シグナル伝達因子の形質膜への局在化や活性の調節などの役割を担っている。一方、本修飾が引き起こすタンパク質の分泌に関する知見は数例が報告されているのみである。本研究により明らかにされた脂質修飾依存的な、新規エクソソーム分泌機構により、TGのみならず、エクソソーム分泌の研究分野が発展することが期待される。またTGは、肝疾患、癌、血栓形成、セリアック病などの原因にもなる。一部の疾患発症の際には、未知の機構でTGの分泌量が上昇しており、疾患発症の関係が指摘されている。また、エクソソームも炎症、癌の転移など様々な疾患に関わっているため、TG関連疾患の解明の一助となる可能性もある。