Bcl(-)2 regulates store-operated Ca(2+) entry to modulate ER stress-induced apoptosis.
Bcl(-)2 regulates store-operated Ca(2+) entry to modulate ER stress-induced apoptosis.
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DOI：
10.1038/s41420-018-0039-4
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发表时间：
2018-12
影响因子：
7
通讯作者：
Shen MR
中科院分区：
文献类型：
--
作者：
Chiu WT;Chang HA;Lin YH;Lin YS;Chang HT;Lin HH;Huang SC;Tang MJ;Shen MR
Ca ~（2+）在介导细胞凋亡中起重要作用。据报道，关键的抗凋亡蛋白Bcl-2调节Ca 2+穿过ER膜的运动，但Bcl-2对Ca 2+水平的确切影响仍有争议。钙池操纵的钙内流（SOCE）是非兴奋性细胞中钙摄取的主要模式，通过消耗内质网中的钙而激活。ER中Ca 2+的消耗导致SOC通道激活剂STIM 1易位至质膜。此后，STIM 1与Orai 1或/和TRPC 1通道结合，迫使它们打开，从而允许Ca 2+进入。此外，已经报道了几种抗癌药物通过SOCE途径诱导癌细胞凋亡。然而，Bcl-2调节SOCE的详细机制还不清楚。在这项研究中，Bcl-2 BH 1结构域内的三个氨基酸的突变产生，以验证Bcl-2在ER应激过程中的Ca 2+处理的作用。Bcl-2突变体（mt）在内质网和线粒体中的亚细胞定位与野生型Bcl-2（WT）相似。我们发现，MT增强毒胡萝卜素和衣霉素诱导的细胞凋亡，通过ER应激介导的细胞凋亡，但不是通过死亡受体和ESTA依赖的细胞凋亡，而WT阻止毒胡萝卜素和衣霉素诱导的细胞凋亡。此外，mt耗尽ER腔中的Ca 2+，也增加了SOCE相关分子的表达。因此，通过SOCE的大量Ca 2+内流有助于caspase激活和凋亡。此外，抑制SOCE或螯合细胞外或细胞内Ca 2+抑制线粒体介导的凋亡。总之，我们的研究结果探讨了Bcl-2在Ca 2+稳态和ER应激的调节中的关键作用。
Ca2+ plays a significant role in linking the induction of apoptosis. The key anti-apoptotic protein, Bcl-2, has been reported to regulate the movement of Ca2+ across the ER membrane, but the exact effect of Bcl-2 on Ca2+ levels remains controversial. Store-operated Ca2+ entry (SOCE), a major mode of Ca2+ uptake in non-excitable cells, is activated by depletion of Ca2+ in the ER. Depletion of Ca2+ in the ER causes translocation of the SOC channel activator, STIM1, to the plasma membrane. Thereafter, STIM1 binds to Orai1 or/and TRPC1 channels, forcing them to open and thereby allow Ca2+ entry. In addition, several anti-cancer drugs have been reported to induce apoptosis of cancer cells via the SOCE pathway. However, the detailed mechanism underlying the regulation of SOCE by Bcl-2 is not well understood. In this study, a three-amino acid mutation within the Bcl-2 BH1 domain was generated to verify the role of Bcl-2 in Ca2+ handling during ER stress. The subcellular localization of the Bcl-2 mutant (mt) is similar to that in the wild-type Bcl-2 (WT) in the ER and mitochondria. We found that mt enhanced thapsigargin and tunicamycin-induced apoptosis through ER stress-mediated apoptosis but not through the death receptor- and mitochondria-dependent apoptosis, while WT prevented thapsigargin- and tunicamycin-induced apoptosis. In addition, mt depleted Ca2+ in the ER lumen and also increased the expression of SOCE-related molecules. Therefore, a massive Ca2+ influx via SOCE contributed to caspase activation and apoptosis. Furthermore, inhibiting SOCE or chelating either extracellular or intracellular Ca2+ inhibited mt-mediated apoptosis. In brief, our results explored the critical role of Bcl-2 in Ca2+ homeostasis and the modulation of ER stress.
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DOI：
10.18632/aging.100459
发表时间：
2012-05
期刊：
Aging
影响因子：
--
作者：
Favaloro B;Allocati N;Graziano V;Di Ilio C;De Laurenzi V
通讯作者：
De Laurenzi V
影响因子：
64.5
作者：
Park CY;Hoover PJ;Mullins FM;Bachhawat P;Covington ED;Raunser S;Walz T;Garcia KC;Dolmetsch RE;Lewis RS
通讯作者：
Lewis RS
影响因子：
11.4
作者：
Dlugosz, Paulina J.;Billen, Lieven P.;Andrews, David W.
通讯作者：
Andrews, David W.
DOI：
10.1152/ajprenal.1997.273.2.f300
发表时间：
1997-08-01
影响因子：
4.2
作者：
Lin, HH;Yang, TP;Tang, MJ
通讯作者：
Tang, MJ
DOI：
10.1073/pnas.91.14.6569
发表时间：
1994-07-05
影响因子：
11.1
作者：
LAM, M;DUBYAK, G;DISTELHORST, CW
通讯作者：
DISTELHORST, CW