Mechanism and regulation of transport-type autophagy

2023 Fiscal Year Final Research Report

• Project Area: Multimode autophagy: Diverse pathways and selectivity
• Project/Area Number: 19H05710
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: Kabuta Tomohiro 国立研究開発法人国立精神・神経医療研究センター, 神経研究所 疾病研究第四部, 室長 (70535765)
• Project Period (FY): 2019-06-28 – 2024-03-31
• Keywords: オートファジー / タンパク質分解 / 核酸分解

Outline of Final Research Achievements

We showed that ATP consumption is required for lysosomal uptake of nucleic acids during RNautophagy/DNautophagy (RDA), but V-ATPase is not required. We found multiple regulatory mechanisms underlying RNautophagy, including an activation mechanism mediated by innate immune receptors and a nucleic acid binding sequence in the cytoplasmic domain of SIDT2. We found a phenomenon in which proteins are directly taken up into lysosomes in an ATP-dependent manner and degraded. We also found that SIDT2 mediates this pathway. Furthermore, we revealed that dysfunction of this degradation mechanism leads to accumulation of proteins within cells, causing neuromuscular diseases.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

マルチモードオートファジーについては不明な点が多かった。本研究ではそのような多様なオートファジー経路の分子機構、制御機構と生理・病態生理的意義の一端を解明した。本研究で明らかとなった分解経路やこれらの経路において機能するタンパク質は、アルツハイマー病・パーキンソン病など、タンパク質蓄積が原因となる神経変性疾患や筋疾患について新たな治療標的となり得る。