Structure of the Human Autophagy Initiating Kinase ULK1 in Complex with Potent Inhibitors

Lazarus, Michael B.; Novotny, Chris J.

doi:10.1021/cb500835z

Cited by 134 publications

(158 citation statements)

References 29 publications

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“…Finally, the structure of the kinase domain of human ULK1 was reported, confirming that it has a canonical protein kinase fold consisting of two lobes (N-lobe and C-lobe) (Fig. 2D) (Lazarus et al, 2015). These studies established the structures of all three core subunits of the autophagy initiation complex except for the IDRs and the interactions constructing the Atg1 complex.…”

Section: Atg101supporting

confidence: 65%

Atg101: Not Just an Accessory Subunit in the Autophagy-initiation Complex

Noda

Mizushima

2016

Cell Struct. Funct.

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ABSTRACT. The Saccharomyces cerevisiae autophagy-initiation complex, Atg1 kinase complex, consists of Atg1, Atg13, Atg17, Atg29, and Atg31, while the corresponding complex in most other eukaryotes, including mammals, is composed of ULK1 (or ULK2), Atg13, FIP200 (also known as RB1CC1), and Atg101. ULKs are homologs of Atg1, and FIP200 is partially homologous to Atg17. However, the sequence of Atg101 is not similar to that of Atg29 or Atg31. Although Atg101 is essential for autophagy and widely conserved in eukaryotes, its precise function and structure have remained largely unknown. Now, structural and cell biological analysis of Atg101 together with its binding partner Atg13 reveal that Atg101 is required for stabilization of "uncapped" Atg13 in most eukaryotes and also for recruitment of downstream Atg proteins through the newly identified WF motif. By contrast, S. cerevisiae has stable "capped" Atg13, which does not require Atg101 for its stabilization. Possible roles for other binding partners such as Atg29, Atg31, and Atg28 in different organisms are also discussed.

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Section: Atg101supporting

confidence: 65%

Atg101: Not Just an Accessory Subunit in the Autophagy-initiation Complex

Noda

Mizushima

2016

Cell Struct. Funct.

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“…38 We propose that the development of more specific inhibitors of ULK1-deubiquitinating enzymes and thus the modulation of ULK1 ubiquitination might represent an alternative strategy to regulate ULK1 function, next to direct inhibition of the kinase activity. Generally, it has been proposed that MTOR inhibitors and other anticancer drugs induce cytoprotective autophagy, ultimately leading to a compromised efficacy of these compounds.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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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.

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“…The structure of ULK1 crystals demonstrates that the R266 residue interacts with the glutamic acid (E) at 191 via a buried salt bridge (Supplementary Figures S8a-c). 41 Both residues are conserved among closely related kinases (Supplementary Figure S8b) and the R266A mutation may alter folding of the kinase domain and impair ULK1 catalytic activity. 42 ATG13 is phosphorylated at serine (S) 318 in a ULK1-dependent manner.…”

Section: ) (D and E)mentioning

confidence: 99%

Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1

et al. 2015

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Reactive oxygen species (ROS) may cause cellular damage and oxidative stress-induced cell death. Autophagy, an evolutionarily conserved intracellular catabolic process, is executed by autophagy (ATG) proteins, including the autophagy initiation kinase Unc-51-like kinase (ULK1)/ATG1. Although autophagy has been implicated to have both cytoprotective and cytotoxic roles in the response to ROS, the role of individual ATG proteins, including ULK1, remains poorly characterized. In this study, we demonstrate that ULK1 sensitizes cells to necrotic cell death induced by hydrogen peroxide (H 2 O 2 ). Moreover, we demonstrate that ULK1 localizes to the nucleus and regulates the activity of the DNA damage repair protein poly (ADP-ribose) polymerase 1 (PARP1) in a kinase-dependent manner. By enhancing PARP1 activity, ULK1 contributes to ATP depletion and death of H 2 O 2 -treated cells. Our study provides the first evidence of an autophagy-independent prodeath role for nuclear ULK1 in response to ROS-induced damage. On the basis of our data, we propose that the subcellular distribution of ULK1 has an important role in deciding whether a cell lives or dies on exposure to adverse environmental or intracellular conditions. Cell Death and Differentiation (2016) 23, 216-230; doi:10.1038/cdd.2015; published online 3 July 2015Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide (H 2 O 2 ), are formed by the incomplete reduction of oxygen during oxidative phosphorylation and other enzymatic processes. ROS are signaling molecules that regulate cell proliferation, differentiation, and survival. 1-3 Accumulation of ROS (i.e., oxidative stress) on exposure to xenobiotic agents or environmental toxins can cause cellular damage and death via apoptotic or nonapoptotic pathways. [4][5][6] Oxidative stress-induced cellular damage and death have been implicated in aging, ischemia-reperfusion injury, inflammation, and the pathogenesis of diseases (e.g., neurodegeneration and cancer). 7 Oxidative stress also contributes to the antitumor effects of many chemotherapeutic drugs, including camptothecin 8,9 and selenite. 10,11 Autophagy, an evolutionarily conserved intracellular catabolic process, involves lysosome-dependent degradation of superfluous and damaged cytosolic organelles and proteins. 12 It is typically upregulated under conditions of perceived stress and in response to cellular damage. The consequence of autophagy activation -whether cytoprotective or cytotoxicappears to depend on the cell type and the nature and extent of stress. Although most studies indicate a cytoprotective role for autophagy, some evidence suggests that it contributes to cell death in response to oxidative stress. [13][14][15][16][17] Studies have also indicated that autophagy may be suppressed in response to oxidative stress, thereby sensitizing certain cells to apoptosis. 18,19 Unc-51-like kinase/autophagy 1 (ULK1/ATG1) is a mammalian serine-threonine kinase that regulates flux through the autophagy pathway by activating the VPS34 PI(3) kinas...

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Structure of the Human Autophagy Initiating Kinase ULK1 in Complex with Potent Inhibitors

Cited by 134 publications

References 29 publications

Atg101: Not Just an Accessory Subunit in the Autophagy-initiation Complex

Atg101: Not Just an Accessory Subunit in the Autophagy-initiation Complex

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

Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1

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