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.

内质膜损伤诱导一系列细胞应答机制以维持稳态，包括依赖ESCRT的膜修复和受损细胞器的自噬清除。既往研究表明，这些系统可能独立运作。本研究揭示，半乳甘露聚糖结合蛋白3（Gal3），一种属于细胞质 lectin 的 β-半乳糖苷聚糖结合家族成员，在功能上和机制上统一并协调ESCRT和自噬反应以应对溶酶体损伤。Gal3及其识别损伤暴露的聚糖的能力对于溶酶体损伤期间关键ESCRT组分ALIX的有效募集至关重要。Gal3和ALIX均为恢复溶酶体功能所必需。在溶酶体损伤修复过程中，Gal3促进了ALIX与下游ESCRT-III效应因子CHMP4之间的相互作用。在溶酶体损伤后的较晚时间点，Gal3调控自噬反应。当这些过程失败时，如在Gal3敲除细胞中，溶酶体替代程序通过TFEB接管。这种分阶段响应的表现，包括膜修复、移除和替代，在由蛋白质性tau蛋白引起的溶酶体损伤模型系统和由结核分枝杆菌引起的吞噬泡寄生模型系统中得到检测。