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      Bcl 2 regulates store-operated Ca 2+ entry to modulate ER stress-induced apoptosis

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          Abstract

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

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          Calcium--a life and death signal.

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            STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane.

            As the sole Ca2+ entry mechanism in a variety of non-excitable cells, store-operated calcium (SOC) influx is important in Ca2+ signalling and many other cellular processes. A calcium-release-activated calcium (CRAC) channel in T lymphocytes is the best-characterized SOC influx channel and is essential to the immune response, sustained activity of CRAC channels being required for gene expression and proliferation. The molecular identity and the gating mechanism of SOC and CRAC channels have remained elusive. Previously we identified Stim and the mammalian homologue STIM1 as essential components of CRAC channel activation in Drosophila S2 cells and human T lymphocytes. Here we show that the expression of EF-hand mutants of Stim or STIM1 activates CRAC channels constitutively without changing Ca2+ store content. By immunofluorescence, EM localization and surface biotinylation we show that STIM1 migrates from endoplasmic-reticulum-like sites to the plasma membrane upon depletion of the Ca2+ store. We propose that STIM1 functions as the missing link between Ca2+ store depletion and SOC influx, serving as a Ca2+ sensor that translocates upon store depletion to the plasma membrane to activate CRAC channels.
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              STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1.

              Store-operated Ca(2+) channels activated by the depletion of Ca(2+) from the endoplasmic reticulum (ER) are a major Ca(2+) entry pathway in nonexcitable cells and are essential for T cell activation and adaptive immunity. After store depletion, the ER Ca(2+) sensor STIM1 and the CRAC channel protein Orai1 redistribute to ER-plasma membrane (PM) junctions, but the fundamental issue of how STIM1 activates the CRAC channel at these sites is unresolved. Here, we identify a minimal, highly conserved 107-aa CRAC activation domain (CAD) of STIM1 that binds directly to the N and C termini of Orai1 to open the CRAC channel. Purified CAD forms a tetramer that clusters CRAC channels, but analysis of STIM1 mutants reveals that channel clustering is not sufficient for channel activation. These studies establish a molecular mechanism for store-operated Ca(2+) entry in which the direct binding of STIM1 to Orai1 drives the accumulation and the activation of CRAC channels at ER-PM junctions.
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                Author and article information

                Contributors
                wtchiu@mail.ncku.edu.tw
                Journal
                Cell Death Discov
                Cell Death Discov
                Cell Death Discovery
                Nature Publishing Group UK (London )
                2058-7716
                26 February 2018
                26 February 2018
                December 2018
                : 4
                : 37
                Affiliations
                [1 ]ISNI 0000 0004 0532 3255, GRID grid.64523.36, Department of Biomedical Engineering, , National Cheng Kung University, ; Tainan, 701 Taiwan
                [2 ]ISNI 0000 0004 0532 3255, GRID grid.64523.36, Institute of Basic Medical Sciences, , National Cheng Kung University, ; Tainan, 701 Taiwan
                [3 ]ISNI 0000 0004 0532 3255, GRID grid.64523.36, Department of Pharmacology, , National Cheng Kung University, ; Tainan, 701 Taiwan
                [4 ]ISNI 0000 0004 0532 3255, GRID grid.64523.36, Department of Physiology, , National Cheng Kung University, ; Tainan, 701 Taiwan
                [5 ]ISNI 0000 0004 0572 9255, GRID grid.413876.f, Department of Obstetrics and Gynecology, , Chi Mei Medical Center, ; Liouying Campus, Tainan, 736 Taiwan
                Author information
                http://orcid.org/0000-0003-0310-0675
                Article
                39
                10.1038/s41420-018-0039-4
                5841437
                151ae739-9d03-4b87-b0b4-a6a946a021aa
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 27 December 2017
                : 8 February 2018
                : 12 February 2018
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                © The Author(s) 2018

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