title: Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1.
abstract: 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 (H2O2). 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 H2O2-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.
authors.affiliation: Pathology Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Pathology Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Iyengar
authors.affiliation: Pathology Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Joo
authors.affiliation: Pathology Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: X J
authors.initials: XJ
authors.lastname: Li-Harms
authors.affiliation: Pathology Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wright
authors.affiliation: Pathology Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Marino
authors.affiliation: Cell and Molecular Biology Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Winborn
authors.affiliation: Structural Biology Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Phillips
authors.affiliation: Cell and Tissue Imaging Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Temirov
authors.affiliation: Cell Biology and Molecular Medicine Department, Rutgers New Jersey Medical School, Newark, NJ, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sciarretta
authors.affiliation: Structural Biology Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kriwacki
authors.affiliation: St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Peng
authors.affiliation: Chemical Biology Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Shelat
authors.affiliation: Pathology Department, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kundu
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D006861:Hydrogen Peroxide; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C112444:Ulk1 protein, mouse