BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival
BAX inhibitor-1 is a Ca2+ channel critically important for immune cell function and survival
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DOI：
10.1038/cdd.2015.115
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发表时间：
2016-02-01
影响因子：
12.4
通讯作者：
Methner, A.
中科院分区：
文献类型：
--
作者：
Lisak, D.;Schacht, T.;Methner, A.
内质网(ER)是细胞内钙离子的主要储存区，在蛋白质的合成和折叠过程中起着重要作用。Bax(BCL2相关的X蛋白)抑制因子-1(BI-1)是一种钙离子泄漏通道，也参与了对蛋白质错误折叠的反应，从而连接了内质网的钙储存和蛋白质折叠功能。我们发现，BI-1基因缺陷小鼠出现白细胞减少和红细胞增多，脾边缘B区B细胞数量增加，核因子-B-kappa(核因子-kappa)的丰度和核转位增加。激活的B细胞轻链增强剂)蛋白，与胞浆和内质网钙离子水平升高相关。当被放入培养中时，纯化的敲除T细胞和B细胞会自发死亡。在此之前，线粒体启动子caspase-9的活性增加，并与线粒体Ca~(2+)水平的显著飙升相关，表明线粒体Ca~(2+)缓冲能力衰竭是体外细胞死亡的根本原因。在体内，依赖T细胞的实验性自身免疫性脑脊髓炎和依赖B细胞的抗体产生减弱，证实了体外结果。这些结果表明，BI-1通过调节淋巴细胞内钙稳态，在适应性免疫系统的功能中发挥重要作用。
The endoplasmic reticulum (ER) serves as the major intracellular Ca2+ store and has a role in the synthesis and folding of proteins. BAX (BCL2-associated X protein) inhibitor-1 (BI-1) is a Ca2+ leak channel also implicated in the response against protein misfolding, thereby connecting the Ca2+ 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-B-kappa (nuclear factor-(kappa). light-chain enhancer of activated B cells) proteins, correlating with increased cytosolic and ER Ca2+ 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 Ca2+ levels, suggesting an exhausted mitochondrial Ca2+ 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 Ca2+ homeostasis in lymphocytes.