PKA-mediated phosphorylation regulates the function of activation-induced deaminase (AID) in B cells
PKA-mediated phosphorylation regulates the function of activation-induced deaminase (AID) in B cells
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DOI：
10.1073/pnas.0509969103
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发表时间：
2006-01-10
影响因子：
11.1
通讯作者：
Dalla-Favera, R
中科院分区：
文献类型：
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作者：
Pasqualucci, L;Kitaura, Y;Dalla-Favera, R
在体液免疫应答过程中，两种不同的基因修饰事件使生发中心（GC） B细胞中的Ig基因多样化：体细胞超突变和类开关重组（CSR）。这两个过程都需要激活诱导胞苷脱氨酶（AID）的活性，这种酶在GC B细胞中特异性表达。然而，调控AID活性的机制在很大程度上是未知的。在这里，我们报道了蛋白激酶A （PKA）磷酸化AID并调节其在GC B细胞中的活性。AID与细胞质中的PKA全酶发生物理相互作用，并在特定残基上被PKA催化亚基磷酸化。CSR需要AID磷酸化，因为两个磷酸化靶点的替代会损害其在aids缺陷B细胞中拯救CSR的能力。药理抑制PKA可阻止小鼠b细胞淋巴瘤细胞系的同型转换相反，通过条件删除PKA调控亚基基因使PKA活性构成的小鼠B细胞表现出增强的CSR。这些发现暗示PKA参与AID功能的调节，并提示T细胞依赖性免疫反应的控制可能通过AID被激活PKA的信号调节。
During humoral immune responses, two distinct genetic modification events diversify the Ig genes in germinal center (GC) B cells: somatic hypermutation and class switch recombination (CSR). Both processes require the activity of activation-induced cytidine deaminase (AID), an enzyme expressed specifically in GC B cells. However, the mechanisms that regulate AID activity are largely unknown. Here we report that protein kinase A (PKA) phosphorylates AID and regulates its activity in GC B cells. AID physically interacts with the PKA holoenzyme in the cytoplasm and is phosphorylated by the PKA catalytic subunit at specific residues. AID phosphorylation is required for CSR, because substitution of the two phosphorylation targets impairs its ability to rescue CSR in AID-deficient B cells. Pharmacologic inhibition of PKA prevents isotype class switching in a murine B-cell lymphoma cell line; conversely, B cells from mice where PKA activity is made constitutive by conditional deletion of the PKA regulatory subunit gene display enhanced CSR. These findings implicate PKA in the regulation of AID function and suggest that the control of T cell-dependent immune responses may be modulated, via AID, by signals that activate PKA.