BAX inhibitor-1 Is a Ca(2+) Channel Critically Important for Immune Cell Function and Survival

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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