Galectin-3 coordinates a cellular system for lysosomal repair and removal

Endomembrane damage elicits a set of cellular responses to maintain homeostasis including ESCRT-dependent membrane repair and autophagic removal of damaged organelles. Previous studies have suggested that these systems may act separately. Here we show that galectin-3 (Gal3), a member of the -galactoside glycan-binding family of cytosolic lectins, functionally and mechanistically unifies and coordinates ESCRT and autophagy responses to lysosomal damage. Gal3 and its capacity to recognize damage-exposed glycans were required for efficient recruitment of the key ESCRT component ALIX during lysosomal damage. Both Gal3 and ALIX were required for restoration of lysosomal function. Gal3 promoted interactions between ALIX and the downstream ESCRT-III effector CHMP4 during lysosomal damage repair. At later time points following lysosomal injury, Gal3 controlled autophagic responses. When these processes failed, as in Gal3 knockout cells, lysosomal replacement program took over through TFEB. Manifestations of this staged response, which includes membrane repair, removal and replacement, were detected in model systems of lysosomal damage inflicted by proteopathic tau and during phagosome parasitism by Mycobacterium tuberculosis.