B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins
B-cell receptor activation inhibits AID expression through calmodulin inhibition of E-proteins
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DOI：
10.1073/pnas.0708220105
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发表时间：
2008-01-29
影响因子：
11.1
通讯作者：
Grundstrom, Thomas
中科院分区：
文献类型：
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作者：
Hauser, Jannek;Sveshnikova, Natalia;Grundstrom, Thomas
当遇到抗原时，b淋巴细胞可以适应产生高度特异性和强效的抗体反应。体细胞超突变在抗体基因的可变区引入点突变，增加了抗体对抗原的亲和力，类开关重组（class switch recombination， CSR）改变了表达的恒定区外显子，从而改变了抗体效应功能。激活诱导胞苷脱氨酶（AID）是体细胞超突变和CSR所必需的致突变抗体多样化酶。必须严格控制致突变的AID酶。在这里，我们发现b细胞受体（BCR）的膜结合抗体的参与，这表明已经达到了良好的抗体亲和力，抑制AID基因表达，钙（Ca2+）信号是这种抑制所必需的。此外，我们发现过表达Ca2+传感器蛋白calmodulin抑制AID基因的表达，并且转录因子E2A是BCR调节AID基因所必需的。E2A在钙调素结合位点发生突变，呈现抗钙调素DNA结合，使AID表达抵抗BCR激活的抑制。因此，BCR激活通过Ca2+/钙调蛋白抑制E2A抑制AID基因表达。
Upon encountering antigens, B-lymphocytes can adapt to produce a highly specific and potent antibody response. Somatic hypermutation, which introduces point mutations in the variable regions of antibody genes, can increase the affinity for antigen, and antibody effector functions can be altered by class switch recombination (CSR), which changes the expressed constant region exons. Activation-induced cytidine deaminase (AID) is the mutagenic antibody diversification enzyme that is essential for both somatic hypermutation and CSR. The mutagenic AID enzyme has to be tightly controlled. Here, we show that engagement of the membrane-bound antibodies of the B-cell receptor (BCR), which signals that good antibody affinity has been reached, inhibits AID gene expression and that calcium (Ca2+) signaling is essential for this inhibition. Moreover, we show that overexpression of the Ca2+ sensor protein calmodulin inhibits AID gene expression, and that the transcription factor E2A is required for regulation of the AID gene by the BCR. E2A mutated in the binding site for calmodulin, and thus showing calmodulin-resistant DNA binding, makes AID expression resistant to the inhibition through BCR activation. Thus, BCR activation inhibits AID gene expression through Ca2+/calmodulin inhibition of E2A.