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

Area of Science:

• Cell Biology
• Immunology
• Calcium Signaling

Background:

• The endoplasmic reticulum (ER) is a key intracellular calcium (Ca2+) store involved in protein synthesis and folding.
• BAX inhibitor-1 (BI-1) functions as a Ca2+ leak channel and is linked to cellular responses against protein misfolding, bridging ER Ca2+ and protein folding functions.

Purpose of the Study:

• To investigate the role of BI-1 in intracellular Ca2+ homeostasis and its impact on the adaptive immune system.

Main Methods:

• Analysis of BI-1-deficient mice, including hematological parameters and immune cell populations.
• In vitro studies of purified T and B lymphocytes to assess cell death and mitochondrial Ca2+ levels.
• In vivo assessment of T-cell-dependent experimental autoimmune encephalomyelitis and B-cell-dependent antibody production.

Main Results:

• BI-1-deficient mice exhibit leukopenia, erythrocytosis, increased splenic marginal zone B cells, and elevated nuclear factor-κB (NF-κB) activity, correlating with increased cytosolic and ER Ca2+ levels.
• Purified BI-1-deficient lymphocytes undergo spontaneous cell death in culture, preceded by increased mitochondrial Ca2+ levels and caspase-9 activation, indicating exhausted mitochondrial Ca2+ buffering.
• Adaptive immune responses, including experimental autoimmune encephalomyelitis and antibody production, are attenuated in BI-1-deficient mice.

Conclusions:

• BI-1 plays a critical role in maintaining intracellular Ca2+ homeostasis within lymphocytes.
• Dysregulation of Ca2+ homeostasis due to BI-1 deficiency compromises lymphocyte survival and adaptive immune function.