The Kelch Repeat Protein KLHDC10 Regulates Oxidative Stress-Induced ASK1 Activation by Suppressing PP5
The Kelch Repeat Protein KLHDC10 Regulates Oxidative Stress-Induced ASK1 Activation by Suppressing PP5
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DOI：
10.1016/j.molcel.2012.09.018
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发表时间：
2012-12-14
期刊：
影响因子：
16
通讯作者：
Ichijo, Hidenori
中科院分区：
文献类型：
--
作者：
Sekine, Yusuke;Hatanaka, Ryo;Ichijo, Hidenori
活性氧（ROS）诱导的凋亡信号调节激酶1（ASK 1）的激活通过激活JNK和p38 MAPK途径在氧化应激介导的细胞死亡中起关键作用。然而，ASK 1在氧化应激反应中的调节机制仍有待阐明。在这里，我们确定了kelch重复蛋白，苗条，作为一个激活剂的ASK 1通过果蝇的错误表达屏幕。我们还进行了蛋白质组学筛选，并揭示了Kelch结构域包含10（KLHDC 10），一种哺乳动物的直系同源物的Slim，与蛋白磷酸酶5（PP 5），这已被证明是应答ROS的应答ASK 1相互作用。KLHDC 10与PP 5的磷酸酶结构域结合并抑制其磷酸酶活性。此外，在Neuro 2A细胞中，KLHDC 10是H2 O2诱导的ASK 1持续激活和细胞死亡所必需的。这些发现表明，Slim/KLHDC 10是ASK 1的激活剂，通过抑制PP 5促进氧化应激诱导的细胞死亡。
Reactive oxygen species (ROS)-induced activation of Apoptosis signal-regulating kinase 1 (ASK1) plays crucial roles in oxidative stress-mediated cell death through the activation of the JNK and p38 MAPK pathways. However, the regulatory mechanism of ASK1 in the oxidative stress response remains to be elucidated. Here, we identified the kelch repeat protein, Slim, as an activator of ASK1 through a Drosophila misexpression screen. We also performed a proteomics screen and revealed that Kelch domain containing 10 (KLHDC10), a mammalian ortholog of Slim, interacted with Protein phosphatase 5 (PP5), which has been shown to inactivate ASK1 in response to ROS. KLHDC10 bound to the phosphatase domain of PP5 and suppressed its phosphatase activity. Moreover, KLHDC10 was required for H2O2-induced sustained activation of ASK1 and cell death in Neuro2A cells. These findings suggest that Slim/KLHDC10 is an activator of ASK1, contributing to oxidative stress-induced cell death through the suppression of PP5.