Impairment of lipid homoeostasis causes accumulation of protein aggregates in the lysosome

• DOI: 10.7554/elife.86194.1
• Publication Date: 2023-05-12T09:24:03Z
• Authors: John Yong; Jacqueline E. Vil...; Ngoc Vu; Matthew A. Kukurugya; Bryson D. Bennett; Magdalena Preciad...; Julia R. Lazzari-...; Kayley Hake; Calvin H. Jan
• Keywords: Proteostasis; Homeostasis

Protein aggregation increases during aging and is a pathological hallmark of many age-related diseases. homeostasis (proteostasis) depends on core network factors directly influencing protein production, folding, trafficking, degradation. Cellular proteostasis also the overall composition proteome numerous environmental variables. Modulating this cellular state can influence stability multiple endogenous proteins, yet contributing to remain incompletely characterized. Here, we perform genome-wide CRISPRi screens elucidate modulators in mammalian cells using fluorescent dye monitor aggregation. These recovered components known network, uncovered link between lipid homeostasis. We subsequently showed that increased uptake and/or disrupted metabolism led lysosomal and, concomitantly, accumulation sphingolipids cholesterol esters. Surprisingly, impairment by dysregulation independent peroxidation or changes stability, nor it caused effects other aspects proteasomal function. results suggest may have primary potentially through direct biophysical mechanisms.