Institute of Biochemistry, Medical Faculty, Justus-Liebig-University, Giessen, Germany.
Mol Cell. 2012 May 25;46(4):472-83. doi: 10.1016/j.molcel.2012.03.003. Epub 2012 Apr 12.
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.
中等浓度的活性氧（ROS）作为核心调节信号分子，而过高浓度的 ROS 则会引发细胞死亡。在这里，我们发现 ROS 诱导的促凋亡激酶 HIPK2 的乙酰化是一种分子机制，它控制着细胞对 ROS 介导的细胞死亡的敏感性和抗性的阈值。在允许的 ROS 浓度下，HIPK2 的 SUMO 化允许 HDAC3 的组成性结合，并使 HIPK2 保持非乙酰化状态。ROS 浓度升高可防止 HIPK2 的 SUMO 化，从而减少 HDAC3 的结合，导致 HIPK2 的乙酰化。重建实验表明，HIPK2 依赖性基因导致 ROS 水平降低。尽管不可乙酰化的 HIPK2 突变体增强了 ROS 诱导的细胞死亡，但乙酰化模拟变体即使在高氧化应激条件下也能确保细胞存活。
