Lysosomal quality control Review.

Abstract

Healthy cells need functional lysosomes to degrade cargo delivered by autophagy and endocytosis. Defective lysosomes can lead to severe conditions such as lysosomal storage diseases (LSDs) and neurodegeneration. To maintain lysosome integrity and functionality, cells have evolved multiple quality control pathways corresponding to different types of stress and damage. These can be divided into five levels: regulation, reformation, repair, removal, and replacement. The different levels of lysosome quality control often work together to maintain the integrity of the lysosomal network. This review summarizes the different quality control pathways and discusses the less-studied area of lysosome membrane protein regulation and degradation, highlighting key unanswered questions in the field.Abbreviation: ALR: autophagic lysosome reformation; CASM: conjugation of ATG8 to single membranes: ER: endoplasmic reticulum; ESCRT: endosomal sorting complexes required for transport; ILF: intralumenal fragment; LSD: lysosomal storage disease; LYTL: lysosomal tubulation/sorting driven by LRRK2; PITT: phosphoinositide-initiated membrane tethering and lipid transport; PE: phosphatidylethanolamine; PLR: phagocytic lysosome reformation; PS: phosphatidylserine; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns4P: phosphatidylinositol-4-phosphate; PtdIns(4,5)P₂: phosphatidylinositol-4,5-bisphosphate; V-ATPase: vacuolar-type H⁺-translocating ATPase.