Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-0861, Japan.
J Biol Chem. 2010 Apr 2;285(14):10597-604. doi: 10.1074/jbc.M109.090142. Epub 2010 Feb 9.
Reactive oxygen species (ROS) generated during cellular metabolism are toxic to cells. As a result, cells must be able to identify ROS as a stress signal and induce stress response pathways that protect cells from ROS toxicity. Recently, peroxiredoxin (Prx)-induced relays of disulfide bond formation have been identified in budding yeast, namely the disulfide bond formation of Yap1, a crucial transcription factor for oxidative stress response, by a specific Prx Gpx3 and by a major Prx Tsa1. Here, we show that an atypical-type Prx Ahp1 can act as a receptor for alkylhydroperoxides, resulting in activation of the Cad1 transcription factor that is homologous to Yap1. We demonstrate that Ahp1 is required for the formation of intermolecular Cad1 disulfide bond(s) in both an in vitro redox system and in cells treated with alkylhydroperoxide. Furthermore, we found that Cad1-dependent transcriptional activation of the HSP82 gene is dependent on Ahp1. Our results suggest that, although the Gpx3-Yap1 pathway contributes more strongly to resistance than the Ahp1-Cad1 pathway, the Ahp1-induced activation of Cad1 can function as a defense system against stress induced by alkylhydroperoxides, possibly including lipid peroxides. Thus, the Prx family of proteins have an important role in determining peroxide response signals and in transmitting the signals to specific target proteins by inducing disulfide bond formation.
细胞代谢过程中产生的活性氧（ROS）对细胞有毒害作用。因此，细胞必须能够识别 ROS 作为应激信号，并诱导应激反应途径，以保护细胞免受 ROS 毒性的侵害。最近，在 budding yeast 中已经鉴定出由过氧化物酶（Prx）诱导的二硫键形成的接力反应，即关键的氧化应激反应转录因子 Yap1 的二硫键形成，由特定的 Prx Gpx3 和主要的 Prx Tsa1 完成。在这里，我们表明一种非典型的 Prx Ahp1 可以作为烷基过氧化物的受体，从而激活与 Yap1 同源的 Cad1 转录因子。我们证明 Ahp1 是在体外氧化还原系统和用烷基过氧化物处理的细胞中形成 Cad1 分子间二硫键所必需的。此外，我们发现 Cad1 依赖的 HSP82 基因的转录激活依赖于 Ahp1。我们的结果表明，尽管 Gpx3-Yap1 途径比 Ahp1-Cad1 途径对抗性的贡献更大，但 Ahp1 诱导的 Cad1 激活可以作为一种防御系统，对抗烷基过氧化物诱导的应激，可能包括脂质过氧化物。因此，过氧化物酶家族的蛋白质在确定过氧化物响应信号以及通过诱导二硫键形成将信号传递到特定的靶蛋白方面具有重要作用。
