Impaired lysophagy in COPD pathogenesis.

• Project/Area Number: 18K08158
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Jikei University School of Medicine
• Principal Investigator: ARAYA JUN 東京慈恵会医科大学, 医学部, 教授 (90468679)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: リソファジー / 慢性閉塞性肺疾患 / 細胞老化 / リソソーム / オートファジー / Galectin3 / TRIM16 / COPD / ガレクチン３

Outline of Final Research Achievements

Cigarette smoke (CS)-induced functional deterioration of lysosomes may be associated with chronic obstructive pulmonary disease (COPD) pathogenesis. Lysosomal membrane permeabilization (LMP) is indicative of damaged lysosomes. Galectin-3 and tripartite motif proteins (TRIM)16 play a cooperative role in recognizing LMP and inducing lysophagy. TRIM16 was involved in CSE-induced lysophagy, with impaired lysophagy associated with lysosomal dysfunction and accelerated cellular senescence. Airway epithelial cells in COPD lungs showed an increase in galectin-3 puncta reflecting lysosomal damage with concomitantly reduced TRIM16 expression levels. HBEC isolated from COPD patients showed reduced TRIM16 but increased galectin-3, and a negative correlation between TRIM16 and galectin-3 protein levels was demonstrated. Increased LMP, which can be attributed to impaired TRIM16-mediated lysophagy, may be responsible for COPD pathogenesis through the enhancement of cellular senescence.

Academic Significance and Societal Importance of the Research Achievements

老化関連呼吸器疾患であるCOPDは、高齢化社会に伴いその患者数は増加し、社会的にも医療経済的にも、その病態解明と有効な治療法の開発は重要な課題である。
我々はCOPD病態における細胞老化の亢進に、リソソーム傷害の蓄積が関与することを見出した。このリソソーム傷害の機序として、TRIM16という蛋白が関与するリソソーム選択的なオートファジー分解である、リソファジーの機能低下の影響を明らかにした。
リソファジー誘導が、COPD病態の制御に有効である可能性が示されており、今後の治療法開発につながる結果と考えている。

Research Products

• [Journal Article] Chaperone-Mediated Autophagy Suppresses Apoptosis via Regulation of the Unfolded Protein Response during Chronic Obstructive Pulmonary Disease Pathogenesis (2020)
  • Author(s): Hosaka Y、Araya J、Fujita Y、Kadota T、Tsubouchi K、Yoshida M、Minagawa S、Hara H、Kawamoto H、Watanabe N、Ito A、Ichikawa A、Saito N、Okuda K、Watanabe J、Takekoshi D、Utsumi H、Hashimoto M、Wakui H、Ito S、Numata T、Mori S、Matsudaira H、Hirano J、Ohtsuka T、Nakayama Katsutoshi、Kuwano K
  • Journal Title: The Journal of Immunology Volume: 205 Issue: 5 Pages: 1256-1267
  • DOI: 10.4049/jimmunol.2000132
  • Peer Reviewed
• [Presentation] TRIM16依存性リソファジーによる喫煙刺激誘導性細胞老化の制御 (2021)
  • Author(s): 保坂 悠介
  • Organizer: 日本呼吸器学学会総会
• [Presentation] COPD病態におけるリソファジーの役割 (2019)
  • Author(s): 荒屋 潤
  • Organizer: 日本呼吸器学会学術講演会
• [Presentation] COPD病態におけるリソファジーの役割 (2019)
  • Author(s): 荒屋 潤
  • Organizer: 第59回日本呼吸器学会学術講演会