Chip Protects Lysosomes From Cln4 Mutantinduced Membrane Damage Juhyung Lee Natalie Chin Jizhong Zou Wan Nur Atiqah Binti Mazli Michal Jarnik Layla Saidi Yue Xu Eutteum Jeong Jessica Suh John Replogle Michael E Ward Juan S Bonifacino Wei Zheng Ling Hao Yihong Ye by Juhyung Lee & Natalie Chin & Jizhong Zou & Wan Nur Atiqah Binti Mazli & Michal Jarnik & Layla Saidi & Yue Xu & Eutteum Jeong & Jessica Suh & John Replogle & Michael E. Ward & Juan S. Bonifacino & Wei Zheng & Ling Hao & Yihong Ye instant download after payment.

Understanding how cells mitigate lysosomal damage is critical for unravelling pathogenic mechanisms of lysosome-related diseases. Here we generate and characterize induced pluripotent stem cell (iPSC)-derived neurons (i3Neuron) bearing ceroid lipofuscinosis neuronal 4 (CLN4)-linked DNAJC5 mutations, which revealed extensive lysosomal abnormality in mutant neurons. In vitro membrane-damaging experiments establish lysosomal damages caused by lysosome-associated CLN4 mutant aggregates, as a critical pathogenic linchpin in CLN4-associated neurodegeneration. Intriguingly, in non-neuronal cells, a ubiquitin-dependent microautophagy mechanism downregulates CLN4 aggregates to counteract CLN4-associated lysotoxicity. Genome-wide CRISPR screens identify the ubiquitin ligase carboxyl terminus of Hsc70-interacting protein (CHIP) as a central microautophagy regulator that confers ubiquitin-dependent lysosome protection. Importantly, CHIP’s lysosome protection function is transferrable: ectopic CHIP improves lysosomal function in CLN4 i3Neurons and efectively alleviates lipofuscin accumulation and cell death in a Drosophila CLN4 disease model. Our study establishes CHIP-mediated microautophagy as a key organelle guardian that preserves lysosome integrity, ofering new insights into therapeutic development for lysosome-related neurodegenerative diseases.