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: D Lisak, T Schacht, A Gawlitza, P Albrecht, O Aktas, B Koop, M Gliem, H H Hofstetter, K Zanger, G Bultynck, J B Parys, H De Smedt, T Kindler, P Adams-Quack, M Hahn, A Waisman, J C Reed, N Hövelmeyer, A Methner
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 23 Issue 2 Pg. 358-68 (Feb 2016) ISSN: 1476-5403 [Electronic] England
• PMID: 26470731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Proteins
• NF-kappa B
• Tmbim6 protein, mouse
• Caspases
• Calcium

Topics

• Active Transport, Cell Nucleus
• Animals
• Apoptosis
• B-Lymphocytes (immunology, metabolism)
• Calcium (metabolism)
• Calcium Signaling
• Caspases (metabolism)
• Cell Survival
• Cytoplasm (metabolism)
• Encephalomyelitis, Autoimmune, Experimental (genetics, immunology)
• Endoplasmic Reticulum (metabolism)
• Enzyme Activation
• Female
• Leukopenia (genetics, immunology)
• Membrane Proteins (physiology)
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (metabolism)
• Obesity (genetics, immunology)
• Spleen (immunology, pathology)
• T-Lymphocytes (immunology, metabolism)