Ca 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 Ca across the ER membrane, but the exact effect of Bcl-2 on Ca levels remains controversial. Store-operated Ca entry (SOCE), a major mode of Ca uptake in non-excitable cells, is activated by depletion of Ca in the ER. Depletion of Ca 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 Ca 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 Ca 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 Ca in the ER lumen and also increased the expression of SOCE-related molecules. Therefore, a massive Ca influx via SOCE contributed to caspase activation and apoptosis. Furthermore, inhibiting SOCE or chelating either extracellular or intracellular Ca inhibited mt-mediated apoptosis. In brief, our results explored the critical role of Bcl-2 in Ca homeostasis and the modulation of ER stress.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841437PMC
http://dx.doi.org/10.1038/s41420-018-0039-4DOI Listing

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