Dynamic regulation of Ero1α and peroxiredoxin 4 localization in the secretory pathway.
Dynamic regulation of Ero1α and peroxiredoxin 4 localization in the secretory pathway.
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DOI：
10.1074/jbc.m113.467845
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发表时间：
2013-10-11
期刊：
影响因子：
--
通讯作者：
Nagata K
中科院分区：
文献类型：
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作者：
Kakihana T;Araki K;Vavassori S;Iemura S;Cortini M;Fagioli C;Natsume T;Sitia R;Nagata K
背景：Ero 1 α和peroxiredoxin 4参与了早期分泌室（ESC）中二硫键的形成，但缺乏已知的保留信号。结果如下：Ero 1 α和peroxiredoxin 4的保留和定位是通过与PDI和ERp44的多步骤和pH依赖性相互作用来维持的。结论：PDI和ERp44对Ero 1 α和peroxiredoxin 4在ESC中的动态定位。意义：四种相互作用物的水平和定位允许不同的ESC氧化还原控制。在早期分泌室（ESC）中，分子伴侣和酶的网络有助于新生蛋白质的氧化折叠。Ero 1黄素蛋白氧化蛋白质二硫键异构酶（PDI），产生H2O2作为副产物。Peroxiredoxin 4（Prx4）可以利用管腔H2O2氧化PDI，从而有利于氧化折叠，同时限制氧化应激。有趣的是，两种ER氧化酶都不包含已知的ER保留信号，这就提出了细胞如何阻止其分泌的问题。在这里，我们表明，这两种蛋白质共享相似的细胞内定位机制。它们的分泌通过与PDI和ERp44的连续相互作用而被阻止，PDI和ERp44是ESC携带的KDEL样基序的两种常驻蛋白。PDI优先结合Ero 1 α，而ERp44同样保留Ero 1 α和Prx4。Ero 1 α和Prx 4的不同结合特性增加了ER氧化还原稳态的稳健性。
Background: Ero1α and peroxiredoxin 4 contribute to disulfide formation in the early secretory compartment (ESC), but lack known retention signals. Results: Retention and localization of Ero1α and peroxiredoxin 4 are maintained through multistep and pH-dependent interactions with PDI and ERp44 in ESC. Conclusion: PDI and ERp44 dynamically localize Ero1α and peroxiredoxin 4 in ESC. Significance: The levels and localization of four interactors allow differential ESC redox control. In the early secretory compartment (ESC), a network of chaperones and enzymes assists oxidative folding of nascent proteins. Ero1 flavoproteins oxidize protein disulfide isomerase (PDI), generating H2O2 as a byproduct. Peroxiredoxin 4 (Prx4) can utilize luminal H2O2 to oxidize PDI, thus favoring oxidative folding while limiting oxidative stress. Interestingly, neither ER oxidase contains known ER retention signal(s), raising the question of how cells prevent their secretion. Here we show that the two proteins share similar intracellular localization mechanisms. Their secretion is prevented by sequential interactions with PDI and ERp44, two resident proteins of the ESC-bearing KDEL-like motifs. PDI binds preferentially Ero1α, whereas ERp44 equally retains Ero1α and Prx4. The different binding properties of Ero1α and Prx4 increase the robustness of ER redox homeostasis.