Cadmium-mediated rescue from ER-associated degradation induces expression of its exporter
Cadmium-mediated rescue from ER-associated degradation induces expression of its exporter
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DOI：
10.1073/pnas.0812114106
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发表时间：
2009-06-23
影响因子：
11.1
通讯作者：
Lee, Jaekwon
中科院分区：
文献类型：
--
作者：
Adle, David J.;Wei, Wenzhong;Lee, Jaekwon
镉是一种剧毒的环境污染物，与多种疾病有关。酵母脱毒镉的主要机制依赖于Pca1（一种p型atp酶）的挤压作用。在Pca1分泌到质膜之前，一个n端降解子靶向Pca1进行降解，而生长培养基中的镉通过阻止Pca1的周转而迅速上调Pca1。在这里，我们展示了内质网相关降解（ERAD）系统，以其在分泌蛋白质量控制中的作用而闻名，意外地负责镉对Pca1表达的调节。在ERAD中，Pca1中一个度的直接镉感应导致Pca1从ERAD中逸出。这种ERAD底物根据细胞需要向分泌能力状态的调节转化说明了质膜蛋白表达控制的机制。酵母可能已经进化出这种调节模式，以牺牲Pca1的不断合成和降解为代价，对镉毒性做出快速反应。部分分泌蛋白的ERAD可能通过信号依赖的调节机制发生，如Pca1所示。
Cadmium is a highly toxic environmental contaminant that has been implicated in various disorders. A major mechanism for cadmium detoxification in the yeast Saccharomyces cerevisiae relies on extrusion via Pca1, a P-type ATPase. While an N-terminal degron targets Pca1 for degradation before its secretion to the plasma membrane, cadmium in the growth media rapidly up-regulates Pca1 by preventing its turnover. Here we show that the endoplasmic reticulum-associated degradation (ERAD) system, known for its role in quality control of secretory proteins, is unexpectedly responsible for the regulation of Pca1 expression by cadmium. Direct cadmium sensing at the ER by a degron in Pca1 leads to an escape of Pca1 from ERAD. This regulated conversion of an ERAD substrate to a secretory competent state in response to a cellular need illustrates a mechanism for expressional control of a plasma membrane protein. Yeast has likely evolved this mode of regulation for a rapid response against cadmium toxicity at the expense of constant synthesis and degradation of Pca1. ERAD of a portion of secretory proteins might occur via signal-dependent regulatory mechanisms as demonstrated for Pca1.