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Cell Death Differ. 2016 Feb;23(2):358-68. doi: 10.1038/cdd.2015.115. Epub 2015 Oct 16.

BAX inhibitor-1 is a Ca(2+) channel critically important for immune cell function and survival.

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Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn) and Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Heinrich Heine Universität Düsseldorf, Department of Neurology, Düsseldorf, Germany.
Center for Anatomy and Brain Research, Düsseldorf, Germany.
Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.
III Medical Clinic, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
Sanford Burnham Institute, La Jolla, CA, USA.


The endoplasmic reticulum (ER) serves as the major intracellular Ca(2+) store and has a role in the synthesis and folding of proteins. BAX (BCL2-associated X protein) inhibitor-1 (BI-1) is a Ca(2+) leak channel also implicated in the response against protein misfolding, thereby connecting the Ca(2+) store and protein-folding functions of the ER. We found that BI-1-deficient mice suffer from leukopenia and erythrocytosis, have an increased number of splenic marginal zone B cells and higher abundance and nuclear translocation of NF-κB (nuclear factor-κ light-chain enhancer of activated B cells) proteins, correlating with increased cytosolic and ER Ca(2+) levels. When put into culture, purified knockout T cells and even more so B cells die spontaneously. This is preceded by increased activity of the mitochondrial initiator caspase-9 and correlated with a significant surge in mitochondrial Ca(2+) levels, suggesting an exhausted mitochondrial Ca(2+) buffer capacity as the underlying cause for cell death in vitro. In vivo, T-cell-dependent experimental autoimmune encephalomyelitis and B-cell-dependent antibody production are attenuated, corroborating the ex vivo results. These results suggest that BI-1 has a major role in the functioning of the adaptive immune system by regulating intracellular Ca(2+) homeostasis in lymphocytes.

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