Lysosomal damage activates AMPK, a regulator of macroautophagy/autophagy and metabolism, and elicits a strong ubiquitination response. Here we show that the cytosolic lectin LGALS9 detects lysosomal membrane breach by binding to lumenal glycoepitopes, and directs both the ubiquitination response and AMPK activation. Proteomic analyses have revealed increased LGALS9 association with lysosomes, and concomitant changes in LGALS9 interactions with its newly identified partners that control ubiquitination-deubiquitination processes. An LGALS9-inetractor, deubiquitinase USP9X, dissociates from damaged lysosomes upon recognition of lumenal glycans by LGALS9. USP9X’s departure from lysosomes promotes K63 ubiquitination and stimulation of MAP3K7/TAK1, an upstream kinase and activator of AMPK hitherto orphaned for a precise physiological function. Ubiquitin-activated MAP3K7/TAK1 controls AMPK specifically during lysosomal injury, caused by a spectrum of membrane-damaging or -permeabilizing agents, including silica crystals, the intracellular pathogen Mycobacterium tuberculosis, TNFSF10/TRAIL signaling, and the anti-diabetes drugs metformin. The LGALS9-ubiquitin system activating AMPK represents a novel signal transduction system contributing to various physiological outputs that are under the control of AMPK, including autophagy, MTOR, lysosomal maintenance and biogenesis, immunity, defense against microbes, and metabolic reprograming.

溶酶体损伤激活了AMPK，AMPK是自噬/自噬和代谢的调节剂，并引起强烈的泛素化反应。在这里，我们表明胞质凝集素LGALS9通过结合到腔糖基表位检测溶酶体膜破坏，并指导泛素化反应和AMPK激活。蛋白质组学分析显示，LGALS9与溶酶体的关联性增加，并且LGALS9与新近识别的控制泛素化-去泛素化过程的伙伴之间相互作用的伴随变化。当LGALS9识别腔聚糖时，LGALS9吸引子，去泛素酶USP9X，从受损的溶酶体中解离。USP9X脱离了溶酶体，促进了K63泛素化并刺激了MAP3K7 / TAK1，后者是迄今为止为精确的生理功能而孤立的AMPK的上游激酶和激活剂。结核分枝杆菌，TNFSF10 / TRAIL信号传导和抗糖尿病药物二甲双胍。激活AMPK的LGALS9-泛素系统代表了一种新颖的信号转导系统，可促进受AMPK控制的各种生理输出，包括自噬，MTOR，溶酶体维持和生物发生，免疫力，抗微生物能力和代谢重编程。