TY - JOUR
T1 - A Redox-Regulated SUMO/Acetylation Switch of HIPK2 Controls the Survival Threshold to Oxidative Stress
AU - de la Vega, L.
AU - Grishina, I.
AU - Moreno, R.
AU - Krüger, M.
AU - Braun, T.
AU - Schmitz, M.L.
PY - 2012/5/25
Y1 - 2012/5/25
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84861452914&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2012.03.003
DO - 10.1016/j.molcel.2012.03.003
M3 - Article
C2 - 22503103
AN - SCOPUS:84861452914
SN - 1097-2765
VL - 46
SP - 472
EP - 483
JO - Molecular Cell
JF - Molecular Cell
IS - 4
ER -