GRASP55 Senses Glucose Deprivation through O-GlcNAcylation to Promote Autophagosome-Lysosome Fusion.
GRASP55 Senses Glucose Deprivation through O-GlcNAcylation to Promote Autophagosome-Lysosome Fusion.
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DOI：
10.1016/j.devcel.2018.03.023
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发表时间：
2018-04-23
影响因子：
11.8
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Zhang X;Wang L;Lak B;Li J;Jokitalo E;Wang Y
高尔基体是分泌途径中蛋白质运输和糖基化的中心枢纽。然而，高尔基体对葡萄糖剥夺的反应是迄今为止未知的。在这里，我们报告，GRASP 55，高尔基堆积蛋白位于中间和反式高尔基池，是O-GlcNAc转移酶OGT在生长条件下的O-GlcNAc酰化。葡萄糖剥夺减少GRASP 55 O-GlcNAc化。De-O-GlcNAc酰化的GRASP 55在高尔基区外形成斑点，其与自噬体和晚期内体/溶酶体共定位。GRASP 55缺失会减少自噬通量并导致自噬体累积，而GRASP 55的O-GlcNAcylation缺陷突变体的表达会加速自噬通量。在生物化学上，GRASP 55与自噬体上的LC 3-II和晚期内体/溶酶体上的LAMP 2相互作用，并作为LC 3-II和LAMP 2之间的桥梁用于自噬体和溶酶体融合;该功能由GRASP 55 O-GlcNAc化负调控。因此，GRASP 55通过O-GlcNAc化来感知葡萄糖水平，并作为系链促进自噬体成熟。Zhang等提供了高尔基体对葡萄糖剥夺的反应和参与自噬体成熟的见解。高尔基体堆积蛋白GRASP 55在葡萄糖饥饿时被脱-O-GlcNAc酰化，并通过LC 3-II和LAMP 2靶向自噬体-溶酶体界面，在那里它作为膜系链起作用以促进自噬体-溶酶体融合。
The Golgi apparatus is the central hub for protein trafficking and glycosylation in the secretory pathway. However, how the Golgi responds to glucose deprivation is so far unknown. Here, we report that GRASP55, the Golgi stacking protein located in medial- and trans-Golgi cisternae, is O-GlcNAcylated by the O-GlcNAc transferase OGT under growth conditions. Glucose deprivation reduces GRASP55 O-GlcNAcylation. De-O-GlcNAcylated GRASP55 forms puncta outside of the Golgi area, which colocalize with autophagosomes and late endosomes/lysosomes. GRASP55 depletion reduces autophagic flux and results in autophagosome accumulation, while expression of an O-GlcNAcylation-deficient mutant of GRASP55 accelerates autophagic flux. Biochemically, GRASP55 interacts with LC3-II on the autophagosomes and LAMP2 on late endosomes/lysosomes and functions as a bridge between LC3-II and LAMP2 for autophagosome and lysosome fusion; this function is negatively regulated by GRASP55 O-GlcNAcylation. Therefore, GRASP55 senses glucose levels through O-GlcNAcylation and acts as a tether to facilitate autophagosome maturation. Zhang et al. provide insight into how the Golgi response to glucose deprivation and participates in autophagosome maturation. The Golgi stacking protein GRASP55 is de-O-GlcNAcylated upon glucose starvation and targeted to the autophagosome-lysosome interface through LC3-II and LAMP2, where it functions as a membrane tether to facilitate autophagosome-lysosome fusion.
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