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AMPK is activated during lysosomal damage via a galectin-ubiquitin signal transduction system.
Autophagy ( IF 13.3 ) Pub Date : 2020-07-25 , DOI: 10.1080/15548627.2020.1788890
Jingyue Jia 1, 2 , Bhawana Bissa 1, 2 , Lukas Brecht 3 , Lee Allers 1, 2 , Seong Won Choi 1, 2 , Yuexi Gu 1, 2 , Mark Zbinden 4 , Mark R Burge 1, 5 , Graham Timmins 1, 6 , Kenneth Hallows 7 , Christian Behrends 3 , Vojo Deretic 1, 2
Affiliation  

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.

Abbreviations

AMPK: AMP-activated protein kinase; APEX2: engineered ascorbate peroxidase 2; ATG13: autophagy related 13; ATG16L1: autophagy related 16 like 1; BMMs: bone marrow-derived macrophages; CAMKK2: calcium/calmodulin dependent protein kinase kinase 2; DUB: deubiquitinase; GPN: glycyl-L-phenylalanine 2-naphthylamide; LLOMe: L-leucyl-L-leucine methyl ester; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MERIT: membrane repair, removal and replacement; MTOR: mechanistic target of rapamycin kinase; STK11/LKB1: serine/threonine kinase 11; TNFSF10/TRAIL: TNF superfamily member 10; USP9X: ubiquitin specific peptidase 9 X-linked



中文翻译:

在溶酶体损伤过程中,AMPK通过半乳凝素-泛素信号转导系统被激活。

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。

缩略语

AMPK:AMP激活的蛋白激酶;APEX2:工程化抗坏血酸过氧化物酶2;ATG13:自噬相关的13;ATG16L1:自噬相关16像1;BMM:骨髓来源的巨噬细胞;CAMKK2:钙/钙调蛋白依赖性蛋白激酶激酶2;DUB:去泛素酶;GPN:甘氨酰-L-苯丙氨酸2-萘酰胺;LLOMe:L-亮氨酰-L-亮氨酸甲酯;MAP1LC3 / LC3:微管相关蛋白1轻链3;MAP3K7 / TAK1:促分裂原激活的蛋白激酶激酶激酶7;优点:膜修复,去除和更换;MTOR:雷帕霉素激酶的机制靶标;STK11 / LKB1:丝氨酸/苏氨酸激酶11;TNFSF10 / TRAIL:TNF超家族成员10; TNF超家族成员10。USP9X:泛素特异性肽酶9 X连锁

更新日期:2020-08-08
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