Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
EMBO Rep. 2023 Dec 6;24(12):e57300. doi: 10.15252/embr.202357300. Epub 2023 Nov 21.
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.
溶酶体是具有降解功能的细胞器和信号中心，它们维持着细胞和组织的内稳态，溶酶体功能障碍与衰老和寿命缩短有关。溶酶体经常受到损伤，但它们的修复机制尚不清楚。在这里，我们证明受损的溶酶体膜通过微自噬（一种称为“微溶酶体吞噬”的过程）进行修复，并确定了该过程起始和结束的关键调节因子。我们发现 AGC 激酶 STK38 是一种新的微溶酶体调节因子。通过支架蛋白 DOK1 的磷酸化，STK38 特异性地被招募到溶酶体上，从而终止微溶酶体吞噬作用，促进 ESCRT 成分的解体。相比之下，微溶酶体的起始涉及 ATG8s 的非典型脂质化，特别是 GABARAP 亚家族，该家族通过与 ALIX 的相互作用，需要 ESCRT 组装。STK38 和 GABARAPs 的缺失分别加速了人类细胞中 DNA 损伤诱导的细胞衰老，并缩短了秀丽隐杆线虫的寿命。因此，微溶酶体受 STK38 和 GABARAPs 的调节，对于维持溶酶体的完整性和防止衰老可能是必不可少的。
