Jiangsu Key Laboratory of Neuroregeneration, Medical School, Nantong University, Nantong, Jiangsu, 226001, China.
J Biol Chem. 2012 Aug 31;287(36):30497-506. doi: 10.1074/jbc.M112.355412. Epub 2012 Jul 5.
Tau exon 10, which encodes the second microtubule-binding repeat, is regulated by alternative splicing. Its alternative splicing generates Tau isoforms with three- or four-microtubule-binding repeats, named 3R-tau and 4R-tau. Adult human brain expresses equal levels of 3R-tau and 4R-tau. Imbalance of 3R-tau and 4R-tau causes Tau aggregation and neurofibrillary degeneration. In the present study, we found that splicing factor SRp55 (serine/arginine-rich protein 55) promoted Tau exon 10 inclusion. Knockdown of SRp55 significantly promoted Tau exon 10 exclusion. The promotion of Tau exon 10 inclusion by SRp55 required the arginine/serine-rich region, which was responsible for the subnucleic speckle localization. Dyrk1A (dual specificity tyrosine-phosphorylated and regulated kinase 1A) interacted with SRp55 and mainly phosphorylated its proline-rich domain. Phosphorylation of SRp55 by Dyrk1A suppressed its ability to promote Tau exon 10 inclusion. Up-regulation of Dyrk1A as in Down syndrome could lead to neurofibrillary degeneration by shifting the alternative splicing of Tau exon 10 to an increase in the ratio of 3R-tau/4R-tau.
外显子 10 编码第二个微管结合重复，受可变剪接调控。其可变剪接产生具有三或四个微管结合重复的 Tau 同工型，分别命名为 3R-tau 和 4R-tau。成人脑中表达等量的 3R-tau 和 4R-tau。3R-tau 和 4R-tau 的失衡导致 Tau 聚集和神经纤维变性。在本研究中，我们发现剪接因子 SRp55（丝氨酸/精氨酸丰富蛋白 55）促进 Tau 外显子 10 的包含。SRp55 的敲低显著促进 Tau 外显子 10 的排除。SRp55 促进 Tau 外显子 10 的包含需要富含精氨酸/丝氨酸的区域，该区域负责亚核斑点定位。Dyrk1A（双特异性酪氨酸磷酸化和调节激酶 1A）与 SRp55 相互作用，主要磷酸化其脯氨酸丰富的结构域。Dyrk1A 对 SRp55 的磷酸化抑制了其促进 Tau 外显子 10 包含的能力。唐氏综合征中 Dyrk1A 的上调可能通过将 Tau 外显子 10 的可变剪接转移到 3R-tau/4R-tau 比值增加，导致神经纤维变性。
