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Proteomics Insights Into Lysosome Biogenesis and Maturation

Katharina Hirn,Sofía Fajardo-Callejón,Dominic Winter

Published 2025 in Proteomics

ABSTRACT

Lysosomes constitute the main degradative organelle of most eukaryotic cells and are capable of breaking down a wide spectrum of biomolecules, including proteins, lipids, glycans, and DNA/RNA. They play crucial roles in the regulation of cellular homeostasis, acting as metabolic signaling centers for the correlation of nutrient availability and biosynthetic processes. The lysosome's importance is highlighted by several human diseases associated with its dysfunction, including both early‐ and late‐onset conditions, dependent on the level of functional impairment. Lysosomal biogenesis presents a multi‐step process consisting of various delivery routes for its individual constituents, enabling strict activity control of the currently known ∼60 lysosomal hydrolases to prevent cellular self‐digestion and proper assembly of the lysosomal membrane. In this review, we recapitulate the contribution of mass spectrometry (MS)‐based proteomics to the characterization of lysosomal biogenesis in the last two decades. The enrichment and proteomic analysis of lysosomes and lysosomal proteins played an invaluable role for the investigation of lysosomes, encompassing the control of lysosomal gene expression, the characterization of sorting/trafficking processes, and the assignment of lysosomal proteins. This has resulted so far in the definition of ∼350 proteins which have been identified to be located in/at lysosomes or are of crucial importance for their function.

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