SOD1 as a Molecular Switch for Initiating the Homeostatic ER Stress Response under Zinc Deficiency
SOD1 as a Molecular Switch for Initiating the Homeostatic ER Stress Response under Zinc Deficiency
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DOI：
10.1016/j.molcel.2013.08.038
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发表时间：
2013-10-10
期刊：
影响因子：
16
通讯作者：
Ichijo, Hidenori
中科院分区：
文献类型：
--
作者：
Homma, Kengo;Fujisawa, Takao;Ichijo, Hidenori
锌是一种必需的微量元素，锌稳态受损与多种人类疾病的发病机制有关。然而，人们对细胞应对锌缺乏的机制知之甚少。我们之前报道过，肌萎缩侧索硬化症 (ALS) 相关的 SOD1 致病性突变体通过与 Derlin-1 的特异性相互作用引起慢性内质网 (ER) 应激，Derlin-1 是 ER 相关降解机制的一个组成部分。此外，我们最近证明这种相互作用对于 ALS 连接的 SOD1 突变体很常见，并且野生型 SOD1 (SOD1(WT)) 包含一个掩蔽的 Derlin-1 结合区 (DBR)。在这里，我们发现，在缺锌条件下，SOD1（WT）采用突变体样构象，暴露DBR并诱导稳态内质网应激反应，包括抑制蛋白质合成和诱导锌转运蛋白。我们得出的结论是，SOD1 具有作为分子开关的功能，可以激活 ER 应激反应，在缺锌条件下的细胞稳态中发挥重要作用。
Zinc is an essential trace element, and impaired zinc homeostasis is implicated in the pathogenesis of various human diseases. However, the mechanisms cells use to respond to zinc deficiency are poorly understood. We previously reported that amyotrophic lateral sclerosis (ALS)-linked pathogenic mutants of SOD1 cause chronic endoplasmic reticulum (ER) stress through specific interactions with Derlin-1, which is a component of the ER-associated degradation machinery. Moreover, we recently demonstrated that this interaction is common to ALS-linked SOD1 mutants, and wild-type SOD1 (SOD1(WT)) comprises a masked Derlin-1 binding region (DBR). Here, we found that, under zinc-deficient conditions, SOD1(WT) adopts a mutant-like conformation that exposes the DBR and induces the homeostatic ER stress response, including the inhibition of protein synthesis and induction of a zinc transporter. We conclude that SOD1 has a function as a molecular switch that activates the ER stress response, which plays an important role in cellular homeostasis under zinc-deficient conditions.