Figure 5. Lysosome repair.

Damaging agents such as lysosomotropic drugs, photodamage, pathogens etc. may inflict varying extent of lysosomal damage, leading to Ca²⁺ efflux from damaged lysosomes. The ESCRT machinery orchestrates repair of the limited lysosomal damage through multiple mechanisms in a coordinated manner. The increase in cytosolic Ca²⁺ is probably sensed by PDCD6 which in turn recruits the ESCRT‐III binding protein ALIX. The ESCRT‐I protein TSG101 and ALIX further recruit the ESCRT‐III machinery together with VPS4 to seal the membrane lesions. Although Ca²⁺ efflux might provide an immediate signal for ESCRT‐III recruitment, the β‐galactoside sensor GAL3, which interacts with ALIX, is required for efficient recruitment of ALIX and ESCRT‐III to the damaged lysosomes. This sealing might be accompanied by formation of ILVs containing the damage, similar to the process of endosomal ILV biogenesis. In macrophages, phagolysosome or lysosome damage triggers activation of the kinase LRRK2. Once activated, LRRK2 phosphorylates the small GTPase Rab8A, and ESCRT‐III is recruited to mediate endolysosomal membrane repair in Ca²⁺‐dependent fashion. Severely damaged lysosomes are engulfed and degraded via lysophagy, initiated by β‐galactoside sensors such as GAL3, which recruits LC3‐containing autophagic membranes.