The University of Chicago, Chicago, Illinois 60637, USA.
Mol Cell Biol. 2011 Sep;31(18):3710-22. doi: 10.1128/MCB.05140-11. Epub 2011 Jul 11.
The regulation of cellular Ca(2+) homeostasis is essential for innumerable physiological and pathological processes. Stanniocalcin 1, a secreted glycoprotein hormone originally described in fish, is a well-established endocrine regulator of gill Ca(2+) uptake during hypercalcemia. While there are two mammalian Stanniocalcin homologs (STC1 and STC2), their precise molecular functions remain unknown. Notably, STC2 is a prosurvival component of the unfolded protein response. Here, we demonstrate a cell-intrinsic role for STC2 in the regulation of store-operated Ca(2+) entry (SOCE). Fibroblasts cultured from Stc2 knockout mice accumulate higher levels of cytosolic Ca(2+) following endoplasmic reticulum (ER) Ca(2+) store depletion, specifically due to an increase in extracellular Ca(2+) influx through store-operated Ca(2+) channels (SOC). The knockdown of STC2 expression in a hippocampal cell line also potentiates SOCE, and the overexpression of STC2 attenuates SOCE. Moreover, STC2 interacts with the ER Ca(2+) sensor STIM1, which activates SOCs following ER store depletion. These results define a novel molecular function for STC2 as a negative modulator of SOCE and provide the first direct evidence for the regulation of Ca(2+) homeostasis by mammalian STC2. Furthermore, our findings implicate the modulation of SOCE through STC2 expression as one of the prosurvival measures of the unfolded protein response.
细胞内钙离子稳态的调节对于无数生理和病理过程都是至关重要的。Stanniocalcin 1 是一种最初在鱼类中描述的分泌糖蛋白激素，是高钙血症期间调节鳃部钙离子摄取的一种成熟的内分泌调节剂。虽然哺乳动物中有两种 Stanniocalcin 同源物（STC1 和 STC2），但其确切的分子功能尚不清楚。值得注意的是，STC2 是未折叠蛋白反应的一种生存促进成分。在这里，我们证明了 STC2 在调节储存操作的钙离子内流（SOCE）中的细胞内固有作用。从小鼠中敲除 Stc2 基因的成纤维细胞在细胞内质网（ER）钙离子储存耗尽后会积累更高水平的细胞质钙离子，具体是由于通过储存操作的钙离子通道（SOC）增加了细胞外钙离子内流。在海马细胞系中敲低 STC2 表达也会增强 SOCE，而过表达 STC2 则会减弱 SOCE。此外，STC2 与 ER 钙离子传感器 STIM1 相互作用，后者在 ER 储存耗尽后激活 SOC。这些结果定义了 STC2 的一个新的分子功能，即作为 SOCE 的负调节剂，并提供了哺乳动物 STC2 调节钙离子稳态的第一个直接证据。此外，我们的发现表明，通过 STC2 表达来调节 SOCE 是未折叠蛋白反应的生存促进措施之一。
