Single-Cell Proteomics Decodes the Cellular Response to Lysosomal Storage in C. elegans Coelomocytes

Lysosomal storage, characterized by the progressive accumulation of undigested substrates in the lysosomal lumen, is a primary driver of various lysosome-related diseases. However, single-cell proteomic remodeling during lysosomal storage remains elusive, and the cellular responses for coping with this condition are poorly understood. Here, we employed deep-coverage single-cell proteomics to analyze C. elegans scavenger cells (coelomocytes) undergoing lysosomal storage. Our analysis revealed profound proteomic remodeling characterized by the massive, asymmetric upregulation of nearly 1000 proteins. We identified a coordinated compensatory response involving the robust induction of endoplasmic reticulum (ER) quality control, including ER unfolded protein response and ER-associated degradation, systemic hyperactivation of the ubiquitin–proteasome system (UPS), and a discordant mitochondrial response featuring concurrent bioenergetic upregulation and severe proteostatic stress. Collectively, this single-cell analysis establishes a high-resolution molecular blueprint of the hierarchical strategies cells employ to survive lysosomal collapse via compensatory quality control mechanisms.