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

被引：39

作者：

Driessen, Stefan ^{[1
]}

Berleth, Niklas ^{[1
]}

Friesen, Olena ^{[1
]}

Loeffler, Antje S. ^{[1
]}

Boehler, Philip ^{[1
]}

Hieke, Nora ^{[1
]}

Stuhldreier, Fabian ^{[1
]}

Peter, Christoph ^{[1
]}

Schink, Kay O. ^{[2
]}

Schultz, Sebastian W. ^{[2
]}

Stenmark, Harald ^{[2
]}

Holland, Petter ^{[3
]}

Simonsen, Anne ^{[3
]}

Wesselborg, Sebastian ^{[1
]}

Stork, Bjoern ^{[1
]}

机构：

[1] Univ Dusseldorf, Inst Mol Med, Dusseldorf, Germany

[2] Norwegian Radium Hosp, Inst Canc Res, Dept Biochem, Oslo, Norway

[3] Univ Oslo, Fac Med, Inst Basic Med Sci, Oslo, Norway

来源：

AUTOPHAGY | 2015年 / 11卷 / 09期

关键词：

autophagy; deubiquitinases; ubiquitination; ULK1; WP1130; DIRECT PHOSPHORYLATION; KINASE ULK1; COMPLEX; AMPK; PROTEINS; ASSOCIATION; ACTIVATION; APOPTOSIS; PATHWAY; AMBRA1;

D O I：

10.1080/15548627.2015.1067359

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1458 / 1470

页数：13

共 38 条

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