title: A redox-regulated SUMO/acetylation switch of HIPK2 controls the survival threshold to oxidative stress.
abstract: Moderate concentrations of reactive oxygen species (ROS) serve as coregulatory signaling molecules, whereas exceedingly high concentrations trigger cell death. Here, we identify ROS-induced acetylation of the proapoptotic kinase HIPK2 as a molecular mechanism that controls the threshold discerning sensitivity from resistance toward ROS-mediated cell death. SUMOylation of HIPK2 at permissive ROS concentrations allows the constitutive association of HDAC3 and keeps HIPK2 in the nonacetylated state. Elevated ROS concentrations prevent SUMOylation of HIPK2 and, consequently, reduce association of HDAC3, thus leading to the acetylation of HIPK2. Reconstitution experiments showed that HIPK2-dependent genes cause decreased ROS levels. Although a nonacetylatable HIPK2 mutant enhanced ROS-induced cell death, an acetylation-mimicking variant ensured cell survival even under conditions of high oxidative stress.
authors.affiliation: Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Giessen, Germany.
authors.forename: Laureano
authors.initials: L
authors.lastname: de la Vega
authors.forename: Inna
authors.initials: I
authors.lastname: Grishina
authors.forename: Rita
authors.initials: R
authors.lastname: Moreno
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.forename: M Lienhard
authors.initials: ML
authors.lastname: Schmitz
mesh_terms: D000107:Acetylation; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D058207:Sumoylation; D000099186:Histone Deacetylase 3
chemical_list: D002352:Carrier Proteins; D006655:Histone Deacetylases; D050505:Mutant Proteins; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D000099186:Histone Deacetylase 3; C115114:HIPK2 protein, human