Article ; Online: Microautophagy regulated by STK38 and GABARAPs is essential to repair lysosomes and prevent aging.
2023 Volume 24, Issue 12, Page(s) e57300
Abstract: Lysosomes are degradative organelles and signaling hubs that maintain cell and tissue homeostasis, and lysosomal dysfunction is implicated in aging and reduced longevity. Lysosomes are frequently damaged, but their repair mechanisms remain unclear. Here, ...
| Abstract | Lysosomes are degradative organelles and signaling hubs that maintain cell and tissue homeostasis, and lysosomal dysfunction is implicated in aging and reduced longevity. Lysosomes are frequently damaged, but their repair mechanisms remain unclear. Here, we demonstrate that damaged lysosomal membranes are repaired by microautophagy (a process termed "microlysophagy") and identify key regulators of the first and last steps. We reveal the AGC kinase STK38 as a novel microlysophagy regulator. Through phosphorylation of the scaffold protein DOK1, STK38 is specifically required for the lysosomal recruitment of the AAA+ ATPase VPS4, which terminates microlysophagy by promoting the disassembly of ESCRT components. By contrast, microlysophagy initiation involves non-canonical lipidation of ATG8s, especially the GABARAP subfamily, which is required for ESCRT assembly through interaction with ALIX. Depletion of STK38 and GABARAPs accelerates DNA damage-induced cellular senescence in human cells and curtails lifespan in C. elegans, respectively. Thus, microlysophagy is regulated by STK38 and GABARAPs and could be essential for maintaining lysosomal integrity and preventing aging. |
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| MeSH term(s) | Animals ; Humans ; Microautophagy ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/metabolism ; Lysosomes/metabolism ; Intracellular Membranes/metabolism ; Endosomal Sorting Complexes Required for Transport/genetics ; Endosomal Sorting Complexes Required for Transport/metabolism ; Autophagy ; Microtubule-Associated Proteins/metabolism ; Apoptosis Regulatory Proteins/metabolism ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism | ||||||||||
| Chemical Substances | Endosomal Sorting Complexes Required for Transport ; GABARAP protein, human ; Microtubule-Associated Proteins ; Apoptosis Regulatory Proteins ; STK38 protein, human (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2023-11-21 | ||||||||||
| Publishing country | England | ||||||||||
| Document type | Journal Article | ||||||||||
| ZDB-ID | 2020896-0 | ||||||||||
| ISSN | 1469-3178 ; 1469-221X | ||||||||||
| ISSN (online) | 1469-3178 | ||||||||||
| ISSN | 1469-221X | ||||||||||
| DOI | 10.15252/embr.202357300 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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