title: BAX inhibitor-1 is a Ca(2+) channel critically important for immune cell function and survival.
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.
authors.affiliation: 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.
authors.forename: D
authors.initials: D
authors.lastname: Lisak
authors.affiliation: 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.
authors.forename: T
authors.initials: T
authors.lastname: Schacht
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Gawlitza
authors.affiliation: Heinrich Heine Universität Düsseldorf, Department of Neurology, Düsseldorf, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Albrecht
authors.affiliation: Heinrich Heine Universität Düsseldorf, Department of Neurology, Düsseldorf, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Aktas
authors.affiliation: Heinrich Heine Universität Düsseldorf, Department of Neurology, Düsseldorf, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Koop
authors.affiliation: Heinrich Heine Universität Düsseldorf, Department of Neurology, Düsseldorf, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Gliem
authors.affiliation: Heinrich Heine Universität Düsseldorf, Department of Neurology, Düsseldorf, Germany.
authors.forename: H H
authors.initials: HH
authors.lastname: Hofstetter
authors.affiliation: Center for Anatomy and Brain Research, Düsseldorf, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Zanger
authors.affiliation: Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.
authors.forename: G
authors.initials: G
authors.lastname: Bultynck
authors.affiliation: Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.
authors.forename: J B
authors.initials: JB
authors.lastname: Parys
authors.affiliation: Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, KU Leuven, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: De Smedt
authors.affiliation: III Medical Clinic, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Kindler
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Adams-Quack
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hahn
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Waisman
authors.affiliation: Sanford Burnham Institute, La Jolla, CA, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Reed
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Hövelmeyer
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Methner
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D007970:Leukopenia / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D016328:NF-kappa B; C490015:Tmbim6 protein, mouse; D020169:Caspases; D002118:Calcium