Dual-specificity Tyrosine Phosphorylation-regulated Kinase 1A (Dyrk1A) Modulates Serine/Arginine-rich Protein 55 (SRp55)-promoted Tau Exon 10 Inclusion

Xiaomin Yin,Nana Jin,Jianlan Gu,Jianhua Shi,Jianhua Zhou,Cheng-Xin Gong,Khalid Iqbal,Inge Grundke-Iqbal,Fei Liu

doi:10.1074/jbc.m112.355412

Abstract

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.

Highlights

Dysregulation of the alternative splicing of Tau exon 10 causes several types of neurodegenerative diseases
We previously reported that Dyrk1A phosphorylates SR proteins SF2/ ASF and SC35 and inhibits their promotion of Tau exon 10 inclusion [13, 14]
3R-tau and 4R-tau generated by alternative splicing of Tau exon 10 are different in modulation of microtubule dynamics and in their cellular distributions (20 –24)

Summary

Background

Dysregulation of the alternative splicing of Tau exon 10 causes several types of neurodegenerative diseases. Dyrk1A interacts with SRp55, mainly phosphorylates its proline-rich domain and inhibits its ability to promote Tau exon 10 inclusion. We found that splicing factor SRp55 (serine/arginine-rich protein 55) promoted Tau exon 10 inclusion. The promotion of Tau exon 10 inclusion by SRp55 required the arginine/serine-rich region, which was responsible for the subnucleic speckle localization. Phosphorylation of SRp55 by Dyrk1A suppressed its ability to promote Tau exon 10 inclusion. Serine- and arginine-rich proteins (SR proteins) are a group of splicing factors and play important roles in alternative splicing of Tau exon 10. We previously reported that Dyrk1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) phosphorylates SR proteins SF2/ ASF (splicing factor 2/alternative splicing factor) and SC35 and inhibits their promotion of Tau exon 10 inclusion [13, 14]. We found that SRp55 promoted the inclusion of Tau exon 10, and phosphorylation of SRp55 by Dyrk1A inhibited this activity

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION