Nuclear localization of NF-ATc by a calcineurin-dependent, cyclosporin-sensitive intramolecular interaction
Nuclear localization of NF-ATc by a calcineurin-dependent, cyclosporin-sensitive intramolecular interaction
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DOI：
10.1101/gad.11.7.824
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发表时间：
1997-04-01
影响因子：
10.5
通讯作者：
Crabtree, GR
中科院分区：
文献类型：
--
作者：
Beals, CR;Clipstone, NA;Crabtree, GR
NF-AT家族转录因子参与调节早期免疫应答基因如IL-2、IL-4、CD40配体和Fas配体响应抗原受体启动的Ca2+/钙调磷酸酶信号。钙调磷酸酶激活导致NF-AT家族成员从细胞质到细胞核的快速易位，这一事件被免疫抑制药物环孢素A和FK506阻断。我们发现易位需要两个冗余的核定位序列，其中一个序列与位于每个NF-AT蛋白氨基末端的保守基序中的磷酸化丝氨酸在分子内结合。NF-ATc中该基序丝氨酸的突变既破坏了分子内相互作用，又导致核定位，这表明NF-AT核进口模型中，钙调磷酸酶的去磷酸化导致两个核定位序列暴露。
The NF-AT family of transcription factors participates in the regulation of early immune response genes such as IL-2, IL-4, CD40 Ligand, and Fas ligand in response to Ca2+/calcineurin signals initiated at the antigen receptor. Calcineurin activation leads to the rapid translocation of NF-AT family members from cytoplasm to nucleus, an event that is blocked by the immunosuppressive drugs cyclosporin A and FK506. We show that translocation requires two redundant nuclear localization sequences and that one sequence is in an intramolceular association with phosphorserines in a conserved motif located at the amino terminus of each NF-AT protein. Mutation of serines in this motif in NF-ATc both disrupts this intramolecular interaction and Leads to nuclear localization, suggesting a model of NF-AT nuclear import in which dephosphorylation by calcineurin causes exposure of two nuclear localization sequences.