Luminal Ca2+ depletion during the unfolded protein response in Xenopus oocytes: cause and consequence.
Luminal Ca2+ depletion during the unfolded protein response in Xenopus oocytes: cause and consequence.
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DOI：
10.1016/j.ceca.2013.01.002
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发表时间：
2013-04
期刊：
影响因子：
4
通讯作者：
Lechleiter JD
中科院分区：
文献类型：
--
作者：
Paredes RM;Bollo M;Holstein D;Lechleiter JD
内质网（Endoplasmic Reticulum，ER）是一种储存钙离子的细胞器，在许多蛋白质的合成、折叠和翻译后修饰中起着关键作用。当新合成的蛋白质的负荷超过其折叠和加工能力时，ER进入应激状态。这激活了一种称为未折叠蛋白质反应（UPR）的信号转导途径，试图恢复体内平衡。ER Ca2+在UPR启动中的确切作用尚未确定。具体而言，它还没有确定是否ER Ca2+失调是ER应激的原因或后果。在这里，我们报告说，部分耗尽ER钙库诱导UPR的显着诱导，并导致正常分泌的蛋白羧肽酶Y的保留。此外，抑制蛋白质糖基化衣霉素迅速诱导ER Ca2+泄漏到胞质溶胶。然而，与emglutamine的translocon阻断抑制衣霉素诱导的Ca 2+释放。此外，Embryonic处理阻断eIF 2 α磷酸化并减少伴侣BiP的表达。这些结果表明，Ca 2+可能是ER蛋白错误折叠的原因和后果。因此，看来ER Ca2+泄漏是引发UPR的重要辅助因素。
The Endoplasmic Reticulum (ER) is a Ca2+ storing organelle that plays a critical role in the synthesis, folding and post-translational modifications of many proteins. The ER enters into a condition of stress when the load of newly synthesized proteins exceeds its folding and processing capacity. This activates a signal transduction pathway called the Unfolded Protein Response (UPR) that attempts to restore homeostasis. The precise role of ER Ca2+ in the initiation of the UPR has not been defined. Specifically, it has not been established whether ER Ca2+ dysregulation is a cause or consequence of ER stress. Here, we report that partial depletion of ER Ca2+ stores induces a significant induction of the UPR, and leads to the retention of a normally secreted protein Carboxypeptidase Y. Moreover, inhibition of protein glycosylation by tunicamycin rapidly induced an ER Ca2+ leak into the cytosol. However, blockade of the translocon with emetine inhibited the tunicamycin-induced Ca2+ release. Furthermore, emetine treatment blocked elF2α phosphorylation and reduced expression of the chaperone BiP. These findings suggest that Ca2+ may be both a cause and a consequence of ER protein misfolding. Thus, it appears that ER Ca2+ leak is a significant co-factor for the initiation of the UPR.
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