A Redox-Regulated SUMO/Acetylation Switch of HIPK2 Controls the Survival Threshold to Oxidative Stress
A Redox-Regulated SUMO/Acetylation Switch of HIPK2 Controls the Survival Threshold to Oxidative Stress
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DOI：
10.1016/j.molcel.2012.03.003
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发表时间：
2012-05-25
期刊：
影响因子：
16
通讯作者：
Schmitz, M. Lienhard
中科院分区：
文献类型：
--
作者：
de la Vega, Laureano;Grishina, Irina;Schmitz, M. Lienhard
中等浓度的活性氧（ROS）作为协同调节信号分子，而过高的浓度会引发细胞死亡。在这里，我们发现ros诱导的凋亡前激酶HIPK2的乙酰化是一种分子机制，它控制着ros介导的细胞死亡抵抗敏感性的阈值。在允许的ROS浓度下，HIPK2的sumo化允许HDAC3的组成性结合，并保持HIPK2处于非乙酰化状态。升高的ROS浓度阻止HIPK2的sumo化，从而减少HDAC3的关联，从而导致HIPK2的乙酰化。重组实验表明，hipk2依赖基因导致ROS水平下降。尽管非乙酰化的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。
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.