Role of kinesin/dynein adaptor JSAP in reactive oxygen species-induced cell death and lysosome positioning

2019 年度 実施状況報告書

• 研究課題/領域番号: 19K16737
• 研究機関: 金沢大学
• 研究代表者: I・KETUT GUNARTA 金沢大学, がん進展制御研究所, 助教 (90838393)
• 研究期間 (年度): 2019-04-01 – 2022-03-31
• キーワード: JSAP / JLP / JSAP1 / Curcumin / Autophagy / Lysosome

研究実績の概要

Cell executes autophagy as a survival system under oxidative stress and the process of autophagy is tightly linked to the activity and the position of the lysosome. Here I will investigate the relationship between JSAP-mediated lysosome trafficking and cell death under acute oxidative stress condition. This study would contribute to the development of a novel therapeutic strategy for cancer. The results of our research in FY 2019 are: (1) We established the role of JLP in curcumin-induced cell death. JLP protect cell from curcumin-induced cell death by mediating autophagosome-lysosome fusion and activation of p38 MAPK.(2) The kinesin-1 heavy chain binding domain (KBD) but not dynactin p150Glued binding domain (DBD) of JLP is required for the regulation of lysosome traficking and autophagy.

現在までの達成度 (区分)

1: 当初の計画以上に進展している

理由

In order to analyze the role of JSAPs in lysosome positioning, JLP or JSAP1 knockdown cells were prepared. While JLP knockdown on cells give an expected phenotype, i.e. impairment of retrograde trafficking of lysosome, JSAP1 knockdown gives a different phenotype. Furthermore, sensitivity of JLP or JSAP1 knockdown cell toward curcumin-induced cell death were similar. This may suggest JLP and JSAP1, despite a high sequence homology, plays a different role in lysosome trafficking.

今後の研究の推進方策

For future analysis of JSAPs-dependent lysosome trafficking, we will elucidate how the involvement of JSAP1 in the lysosome trafficking. For this purpose, knockdown and Crispr/Cas9-mediated knockout of JSAP1 gene in the cell model will be generated. Rescue experiment will be done in order to understand the function of JSAP1 in lysosome trafficking, autophagy and curcumin-induced cell death. By understanding the role of the two protein, we may able to clarify how lysosome trafficking is regulated under certain context.

研究成果

• [雑誌論文] Protective role of c-Jun NH2-terminal kinase-associated leucine zipper protein (JLP) in curcumin-induced cancer cell death (2020)
  • 著者名/発表者名: Jambaldorj Boldbaatar, I Ketut Gunarta, Ryusuke Suzuki, Purev Erdenebaatar, Gantulga Davaakhu. Hirohiko Hohjoh, Katsuji Yoshioka
  • 雑誌名: Biochemical and Biophysical Research Communication 巻: 522 ページ: 697~703
  • DOI: 10.1016/j.bbrc.2019.11.154.
  • 査読あり / オープンアクセス / 国際共著
• [雑誌論文] Functional role of c-Jun NH2-terminal kinase-associated leucine zipper protein (JLP) in lysosome localization and autophagy (2020)
  • 著者名/発表者名: Ryusuke Suzuki, I Ketut Gunarta, Jambaldorj Boldbaatar, Purev Erdenebaatar, Ravdandorj Odongoo, Katsuji Yoshioka
  • 雑誌名: Drug Discoveries & Therapeutics 巻: 14(1) ページ: 35~41
  • DOI: 10.5582/ddt.2020.01001
  • 査読あり / オープンアクセス / 国際共著
• [学会発表] Role of JLP in ROS-induced cell death (2019)
  • 著者名/発表者名: I Ketut Gunarta
  • 学会等名: 1st Ganken Colloquium For Young Scientist
  • 招待講演
• [学会発表] Role of JLP in reactive oxygen species (ROS)-induced cell death and lysosome positioning (2019)
  • 著者名/発表者名: I Ketut Gunarta
  • 学会等名: The 42nd Annual Meeting of the Molecular Biology Society of Japan
  • 国際学会
• [学会発表] Protective role of JLP-dependent lysosome positioning in reactive oxygen species (ROS)-induced cell death (2019)
  • 著者名/発表者名: I Ketut Gunarta
  • 学会等名: International Symposium on Tumor Biology/Joint Symposium of KUCRI and Duke-NUS
  • 招待講演