Microautophagy regulated by STK38 and GABARAPs is essential to repair lysosomes and prevent aging

• Published in: EMBO reports 2023-12, Vol.24 (12), p.e57300-n/a
• Main Authors: Ogura, Monami, Kaminishi, Tatsuya, Shima, Takayuki, Torigata, Miku, Bekku, Nao, Tabata, Keisuke, Minami, Satoshi, Nishino, Kohei, Nezu, Akiko, Hamasaki, Maho, Kosako, Hidetaka, Yoshimori, Tamotsu, Nakamura, Shuhei
• Format: Article
• Language: English
• Subjects: Aging; Animals; Apoptosis Regulatory Proteins - metabolism; Autophagy; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Damage; Depletion; DNA damage; Dok1 protein; Endosomal Sorting Complexes Required for Transport - genetics; Endosomal Sorting Complexes Required for Transport - metabolism; ESCRT; GABARAP protein; Homeostasis; Humans; Integrity; Intracellular Membranes - metabolism; Kinases; Life span; lysosome; Lysosomes; Lysosomes - metabolism; Microautophagy; Microtubule-Associated Proteins - metabolism; non‐canonical ATG8 lipidation; Organelles; Phosphorylation; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein-serine kinase; Proteins; Senescence
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202357300

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. Synopsis Lysosomes are repaired by ESCRT‐driven microautophagy, and STK38 and GABARAPs are key regulators of this process by recruiting ESCRTs to lysosomes. These regulators are essential to maintain lysosomal integrity and prevent aging. STK38 and GABARAP family proteins regulate repair of lysosomes by ESCRT‐driven microautophagy termed “microlysophagy”. STK38 and its phosphorylation target DOK1 regulate VPS4 recruitment to lysosomes. Non‐canonically lipidated GABARAPs are required for initiation of ESCRT assembly by interacting with ALIX. Depletion of STK38 or GABARAPs accelerates cellular senescence and curtails lifespan. Lysosomes are repaired by ESCRT‐driven microautophagy, and STK38 and GABARAPs are key regulators of this process by recruiting ESCRTs to lysosomes. These regulators are essential to maintain lysosomal integrity and prevent aging.