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

SummaryModerate 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.

Graphical AbstractFigure optionsDownload high-quality image (189 K)Download as PowerPoint slideHighlights
► HIPK2 SUMOylation enhances binding of HDAC3 and keeps it in the nonacetylated state
► Oxidative stress causes de-SUMOylation of HIPK2 and thus results in its acetylation
► Acetylation of HIPK2 restricts its ability to trigger ROS-mediated cell death