title: Deubiquitinase inhibition by WP1130 leads to ULK1 aggregation and blockade of autophagy.
abstract: 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.
authors.affiliation: a Institute of Molecular Medicine; Heinrich-Heine-University ; Düsseldorf , Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Drießen
authors.affiliation: a Institute of Molecular Medicine; Heinrich-Heine-University ; Düsseldorf , Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Berleth
authors.affiliation: a Institute of Molecular Medicine; Heinrich-Heine-University ; Düsseldorf , Germany.
authors.forename: Olena
authors.initials: O
authors.lastname: Friesen
authors.affiliation: a Institute of Molecular Medicine; Heinrich-Heine-University ; Düsseldorf , Germany.
authors.forename: Antje S
authors.initials: AS
authors.lastname: Löffler
authors.affiliation: a Institute of Molecular Medicine; Heinrich-Heine-University ; Düsseldorf , Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Böhler
authors.affiliation: a Institute of Molecular Medicine; Heinrich-Heine-University ; Düsseldorf , Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Hieke
authors.affiliation: a Institute of Molecular Medicine; Heinrich-Heine-University ; Düsseldorf , Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Stuhldreier
authors.affiliation: a Institute of Molecular Medicine; Heinrich-Heine-University ; Düsseldorf , Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Peter
authors.affiliation: b Department of Biochemistry ; Institute for Cancer Research; The Norwegian Radium Hospital ; Oslo , Norway.
authors.forename: Kay O
authors.initials: KO
authors.lastname: Schink
authors.affiliation: b Department of Biochemistry ; Institute for Cancer Research; The Norwegian Radium Hospital ; Oslo , Norway.
authors.forename: Sebastian W
authors.initials: SW
authors.lastname: Schultz
authors.affiliation: b Department of Biochemistry ; Institute for Cancer Research; The Norwegian Radium Hospital ; Oslo , Norway.
authors.forename: Harald
authors.initials: H
authors.lastname: Stenmark
authors.affiliation: c Institute of Basic Medical Sciences; Faculty of Medicine; University of Oslo ; Oslo , Norway.
authors.forename: Petter
authors.initials: P
authors.lastname: Holland
authors.affiliation: c Institute of Basic Medical Sciences; Faculty of Medicine; University of Oslo ; Oslo , Norway.
authors.forename: Anne
authors.initials: A
authors.lastname: Simonsen
authors.affiliation: a Institute of Molecular Medicine; Heinrich-Heine-University ; Düsseldorf , Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wesselborg
authors.affiliation: a Institute of Molecular Medicine; Heinrich-Heine-University ; Düsseldorf , Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Stork
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D000071189:Autophagy-Related Protein-1 Homolog; D003487:Cyanoacrylates / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D003487:Cyanoacrylates; D047908:Intracellular Signaling Peptides and Proteins; D066329:Protein Aggregates; D011725:Pyridines; C519751:degrasyn; D049452:Green Fluorescent Proteins; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; D064570:Ubiquitin-Specific Proteases
keywords: ULK1; WP1130; autophagy; deubiquitinases; ubiquitination