Deubiquitinase inhibition by WP1130 leads to ULK1 aggregation and blockade of autophagy

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.

自噬（Autophagy）是一类细胞内降解过程，既参与正常细胞稳态的维持，也与疾病状态密切相关。近年来，调控该过程的分子机制已得到阐明。由丝氨酸/苏氨酸蛋白激酶ULK1以及衔接蛋白ATG13、RB1CC1和ATG101组成的ULK1激酶复合物（ULK1 kinase complex），在自噬起始的调控中发挥核心作用。该复合物的活性又受到多种营养或能量感应激酶的调控，包括MTOR、AMPK与AKT。然而，除磷酸化修饰外，已有研究证实ULK1的泛素化修饰可正向调控其功能。本研究发现，化合物WP1130通过抑制去泛素化酶（deubiquitinases），可使ULK1泛素化水平升高、ULK1向集聚体（aggresomes）转运，并抑制ULK1的活性。此外，WP1130还可阻断自噬流（autophagic flux）。因此，WP1130处理或许可作为一种高效手段，用以抑制自噬起始相关的ULK1激酶复合物及自噬过程。