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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.

Author information

1
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.
2
Heinrich Heine Universität Düsseldorf, Department of Neurology, Düsseldorf, Germany.
3
Center for Anatomy and Brain Research, Düsseldorf, Germany.
4
Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.
5
III Medical Clinic, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
6
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
7
Sanford Burnham Institute, La Jolla, CA, USA.

Abstract

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.

PMID:
26470731
PMCID:
PMC4716298
DOI:
10.1038/cdd.2015.115
[Indexed for MEDLINE]
Free PMC Article

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