Muscleblind proteins regulate alternative splicing
Muscleblind proteins regulate alternative splicing
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DOI：
10.1038/sj.emboj.7600300
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发表时间：
2004-08-04
期刊：
影响因子：
11.4
通讯作者：
Cooper, TA
中科院分区：
文献类型：
--
作者：
Ho, TH;Charlet-B, N;Cooper, TA
虽然肌盲（MBNL）蛋白家族与强直性肌营养不良（DM）有关，但这些蛋白的特异性功能尚未报道。RNA介导的DM发病机制模型的一个关键特征是特异性前mRNA靶点的剪接被破坏。在这里，我们证明了MBNL蛋白调节两个前mRNA的选择性剪接，这两个前mRNA在DM中被错误调节，即心肌肌钙蛋白T（cTNT）和胰岛素受体（IR）。替代cTNT和IR外显子也由CELF蛋白调节，其先前与DM发病机制有关。MBNL蛋白促进cTNT和IR选择性外显子的相反剪接模式，这两者都被CELF蛋白拮抗。CELF-和MBNL-结合位点是不同的，并且MBNL的调节不需要CELF-结合位点。结果与DM发病机制一致，其中扩增的重复序列导致MBNL的损失和/或CELF活性的增加，导致特异性前mRNA靶的可变剪接的错误调节。
Although the muscleblind (MBNL) protein family has been implicated in myotonic dystrophy (DM), a specific function for these proteins has not been reported. A key feature of the RNA-mediated pathogenesis model for DM is the disrupted splicing of specific pre-mRNA targets. Here we demonstrate that MBNL proteins regulate alternative splicing of two pre-mRNAs that are misregulated in DM, cardiac troponin T (cTNT) and insulin receptor (IR). Alternative cTNT and IR exons are also regulated by CELF proteins, which were previously implicated in DM pathogenesis. MBNL proteins promote opposite splicing patterns for cTNT and IR alternative exons, both of which are antagonized by CELF proteins. CELF- and MBNL-binding sites are distinct and regulation by MBNL does not require the CELF- binding site. The results are consistent with a mechanism for DM pathogenesis in which expanded repeats cause a loss of MBNL and/or gain of CELF activities, leading to misregulation of alternative splicing of specific pre-mRNA targets.