A Redox-Regulated SUMO/Acetylation Switch of HIPK2 Controls the Survival Threshold to Oxidative Stress

Laureano de la Vega, Inna Grishina, Rita Moreno, Marcus Krüger, Thomas Braun, M. Lienhard Schmitz

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

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.

Original languageEnglish
Pages (from-to)472-483
Number of pages12
JournalMolecular Cell
Volume46
Issue number4
DOIs
StatePublished - 25 May 2012
Externally publishedYes

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