Deubiquitinase inhibition by WP1130 leads to ULK1 aggregation and blockade of autophagy
Deubiquitinase inhibition by WP1130 leads to ULK1 aggregation and blockade of autophagy
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DOI：
10.1080/15548627.2015.1067359
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发表时间：
2015-09-01
期刊：
影响因子：
13.3
通讯作者：
Stork, Bjoern
中科院分区：
文献类型：
--
作者：
Driessen, Stefan;Berleth, Niklas;Stork, Bjoern
自噬是一种细胞内降解过程，参与细胞内稳态和疾病环境。近年来，控制这一过程的分子机制已被阐明。由丝氨酸/苏氨酸蛋白激酶ULK 1和衔接蛋白ATG 13、RB 1CC 1和ATG 101组成的ULK 1激酶复合物主要参与自噬起始的调节。这种复合物又受到不同营养或能量敏感激酶（包括MTOR、AMPK和AKT）活性的调节。然而，除了磷酸化过程之外，已经提出ULK 1的泛素化积极影响ULK 1功能。在这里，我们报告了化合物WP 1130对去泛素化酶的抑制导致ULK 1泛素化增加，ULK 1转移到侵袭体，以及ULK 1活性的抑制。此外，WP 1130可以阻断自噬通量。因此，用WP 1130治疗可能代表抑制自噬起始ULK 1复合物和自噬的有效工具。
Autophagy represents an intracellular degradation process which is involved in both regular cell homeostasis and disease settings. In recent years, the molecular machinery governing this process has been elucidated. The ULK1 kinase complex consisting of the serine/threonine protein kinase ULK1 and the adapter proteins ATG13, RB1CC1, and ATG101, is centrally involved in the regulation of autophagy initiation. This complex is in turn regulated by the activity of different nutrient- or energy-sensing kinases, including MTOR, AMPK, and AKT. However, next to phosphorylation processes it has been suggested that ubiquitination of ULK1 positively influences ULK1 function. Here we report that the inhibition of deubiquitinases by the compound WP1130 leads to increased ULK1 ubiquitination, the transfer of ULK1 to aggresomes, and the inhibition of ULK1 activity. Additionally, WP1130 can block the autophagic flux. Thus, treatment with WP1130 might represent an efficient tool to inhibit the autophagy-initiating ULK1 complex and autophagy.