Lysosomal damage response mechanism through autophagy independent function of LC3

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02428
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Nara Medical University (2023); Osaka University (2021-2022)
• Principal Investigator: Nakamura Shuhei 奈良県立医科大学, 医学部, 教授 (00510611)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: リソソーム / LC3 / TFEB / オートファジー

Outline of Final Research Achievements

Damaged lysosomes are detrimental to cells. While we had previously found that the master transcription factor for lysosomal biogenesis, TFEB, is activated upon lysosomal damage, that this is essential for damaged lysosome repair, and that this activation requires a non-autophagic function of the autophagy regulator LC3 (Nat Cell Biol, 2020), the details of this function remained unclear. In this study, we found that LC3 paralogues, together with the ESCRT complex, are responsible for repair of damaged membranes (EMBO Rep, 2023). We also identified a novel target of TFEB, HKDC1, and found that it acts in lysosomal and mitochondrial homeostasis (PNAS, 2024).

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

老化過程や様々な加齢性疾患で損傷リソソームの増加が見られているが、損傷リソソームが老化の原因なのか結果なのかはよく分かっていない。本研究で新たに明らかにしたLC3パラログやHKDC1の抑制によって損傷リソソームが増加し、個体老化あるいは細胞老化の亢進がみられたことから、損傷リソソームが老化の要因の一旦になっている可能性が示唆された(EMBO Rep, 2023; PNAS, 2024)。今後これら因子の機能解析をさらに進めることでリソソーム損傷を伴う老化や加齢性疾患を抑制する新たな手法の確立につながる可能性がある。