14-3-3 Binding to ataxin-1(ATXN1) regulates its dephosphorylation at Ser-776 and transport to the nucleus.
14-3-3 Binding to ataxin-1(ATXN1) regulates its dephosphorylation at Ser-776 and transport to the nucleus.
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DOI：
10.1074/jbc.m111.238527
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发表时间：
2011-10-07
期刊：
影响因子：
--
通讯作者：
Orr HT
中科院分区：
文献类型：
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作者：
Lai S;O'Callaghan B;Zoghbi HY;Orr HT
背景：聚谷氨酰胺疾病相关蛋白Ataxin-1 Ser-776位点的磷酸化调节其功能。结果：14-3-3结合通过阻断pS776的去磷酸化来稳定Ataxin-1，并阻碍Ataxin-1向细胞核的转运。结论：14-3-3必须与Ataxin-1解离才能转运至细胞核。意义：14-3-3通过保护Ser-776磷酸化和Ataxin-1进入细胞核调节Ataxin-1功能。脊髓小脑性共济失调1型（SCA1）是一种致命的神经退行性疾病，由ATXN1中聚谷氨酰胺束的扩张引起。SCA1的一个重要病理部位是小脑浦肯野神经元，突变的ATXN1必须进入细胞核才能引起疾病。在SCA1中，ATXN1 Ser-776位点的磷酸化调节疾病。有趣的是，Ser-776位于ATXN1的一个区域内，该区域包含几个功能基元，包括14-3-3的结合位点和剪接因子RBM17和U2AF65。ATXN1与这些蛋白的相互作用被认为是由Ser-776的磷酸化状态调节的。此外，Ser-776与ATXN1中的NLS相邻。虽然pS776-ATXN1在小脑细胞核提取物中富集，但14-3-3绝大多数存在于细胞质部分。我们发现细胞质pS776-ATXN1的去磷酸化由于其位于14-3-3复合物中而被阻断。此外，数据表明14-3-3与细胞质ATXN1的结合阻碍了其向细胞核的运输，这表明14-3-3必须与ATXN1分离才能将ATXN1运输到细胞核。与这一假设一致的观察结果是，一旦进入细胞核，pS776就能够被去磷酸化。有证据表明，PP2A是哺乳动物小脑中的pS776-ATXN1磷酸酶。在细胞核中，我们提出PP2A对pS776-ATXN1的去磷酸化调节了ATXN1与剪接因子RBM17和U2AF65的相互作用。
Background: Phosphorylation at Ser-776 of the polyglutamine disease-associated protein Ataxin-1 modulates its function. Results: 14-3-3 binding stabilizes Ataxin-1 by blocking dephosphorylation of pS776 and impedes Ataxin-1 transport to the nucleus. Conclusion: 14-3-3 must disassociate from Ataxin-1 for its transport to the nucleus. Significance: 14-3-3 regulates Ataxin-1 function by protecting phosphorylation of Ser-776 and Ataxin-1 entry into the nucleus. Spinocerebellar ataxia type 1 (SCA1) is a lethal neurodegenerative disorder caused by expansion of a polyglutamine tract in ATXN1. A prominent site of pathology in SCA1 is cerebellar Purkinje neurons where mutant ATXN1 must enter the nucleus to cause disease. In SCA1, phosphorylation of ATXN1 at Ser-776 modulates disease. Interestingly, Ser-776 is located within a region of ATXN1 that harbors several functional motifs including binding sites for 14-3-3, and splicing factors RBM17 and U2AF65. The interaction of ATXN1 with these proteins is thought to be regulated by the phosphorylation status of Ser-776. In addition, Ser-776 is adjacent to the NLS in ATXN1. Although pS776-ATXN1 is enriched in nuclear extracts of cerebellar cells, the vast majority of 14-3-3 is in the cytoplasmic fraction. We found that dephosphorylation of cytoplasmic pS776-ATXN1 is blocked by virtue of it being in a complex with 14-3-3. In addition, data suggest that binding of 14-3-3 to cytoplasmic ATXN1 impeded its transport to the nucleus, suggesting that 14-3-3 must disassociate from ATXN1 for transport of ATXN1 to the nucleus. Consistent with this hypothesis is the observation that once in the nucleus pS776 is able to be dephosphorylated. Evidence is presented that PP2A is the pS776-ATXN1 phosphatase in the mammalian cerebellum. In the nucleus, we propose that dephosphorylation of pS776-ATXN1 by PP2A regulates the interaction of ATXN1 with the splicing factors RBM17 and U2AF65.