Ubiquitin-like Sequence in ASK1 Plays Critical Roles in the Recognition and Stabilization by USP9X and Oxidative Stress-Induced Cell Death
Ubiquitin-like Sequence in ASK1 Plays Critical Roles in the Recognition and Stabilization by USP9X and Oxidative Stress-Induced Cell Death
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DOI：
10.1016/j.molcel.2009.10.016
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发表时间：
2009-12-11
期刊：
影响因子：
16
通讯作者：
Ichijo, Hidenori
中科院分区：
文献类型：
--
作者：
Nagai, Hiroaki;Noguchi, Takuya;Ichijo, Hidenori
泛素化是一种重要的翻译后修饰，可调节各种细胞过程，包括信号转导。然而，人们对泛素化在 MAPK 通路调节中的生理作用知之甚少。在这里，我们确定去泛素化酶 USP9X 作为 ASK1 的结合伴侣，通过激活 JNK 和 p38 MAPK 途径介导氧化应激诱导的细胞死亡。在去泛素化酶识别泛素的过程中，泛素 C 末端串联甘氨酸-甘氨酸序列的重要性已被提出。有趣的是，ASK1 含有 6 个与泛素 C 末端 (LRLRGG) 相同的氨基酸，并且 ASK1 的 GG 序列是 USP9X-ASK1 相互作用所必需的。我们还发现 USP9X 与氧化应激激活的 ASK1 相互作用，并阻止其发生泛素依赖性降解。在 USP9X 缺陷细胞中，氧化应激诱导的 JNK 激活和随后的细胞死亡减少。这些结果表明，USP9X 依赖性的激活 ASK1 的稳定性在氧化应激诱导的细胞死亡中发挥着至关重要的作用。
Ubiquitination is an important posttranslational modification that regulates various cellular processes, including signal transduction. However, physiological roles of ubiquitination in the regulation of MAPK pathways are poorly understood. Here, we identified the deubiquitinating enzyme USP9X as a binding partner of ASK1 that mediates oxidative stress-induced cell death through activation of the JNK and p38 MAPK pathways. In the recognition of ubiquitin by deubiquitinating enzymes, the importance of a tandem glycine-glycine sequence in the ubiquitin C terminus has been suggested. Interestingly, ASK1 contains six amino acids identical to the ubiquitin C terminus (LRLRGG), and the GG sequence of ASK1 was required for the USP9X-ASK1 interaction. We also found that USP9X interacted with oxidative stress-activated ASK1 and prevented it from undergoing ubiquitin-dependent degradation. In USP9X-deficient cells, oxidative stress-induced JNK activation and subsequent cell death were reduced. These results demonstrate that USP9X-dependent stabilization of activated ASK1 plays a crucial role in oxidative stress-induced cell death.