The RNA-binding protein Staufen1 is increased in DM1 skeletal muscle and promotes alternative pre-mRNA splicing.
The RNA-binding protein Staufen1 is increased in DM1 skeletal muscle and promotes alternative pre-mRNA splicing.
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DOI：
10.1083/jcb.201108113
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发表时间：
2012-03-19
期刊：
影响因子：
--
通讯作者：
Jasmin BJ
中科院分区：
文献类型：
--
作者：
Ravel-Chapuis A;Bélanger G;Yadava RS;Mahadevan MS;DesGroseillers L;Côté J;Jasmin BJ
Staufen 1与具有扩展的CUG重复序列的mRNA相互作用，并促进其核输出和翻译，同时也促进其他mRNA的选择性剪接。在强直性肌营养不良1型（DM 1）中，具有扩增的CUG重复序列（CUGexp）的强直性肌营养不良蛋白激酶信使核糖核酸（RNA; mRNA）在细胞核中聚集，并通过螯合和/或错误调节RNA结合蛋白对细胞产生毒性，导致异常选择性剪接。在本文中，我们发现RNA结合蛋白Staufen 1在DM 1小鼠模型和患者的骨骼肌中显著特异性增加。我们发现Staufen 1与突变的CUGexp mRNA相互作用，并促进它们的核输出和翻译。这种作用主要依赖于Staufen 1的第三个双链RNA结合结构域和Staufen 1通过其核定位信号穿梭进入细胞核。此外，我们还发现了Staufen 1在剪接调控中的新作用。Staufen 1的过表达挽救了已知在DM 1中异常剪接的两个关键前mRNA的选择性剪接，表明其表达增加代表了对病理的适应性反应。总而言之，我们的研究结果揭示了Staufen 1在剪接调控中的新功能，并表明它可能积极调节复杂的DM 1表型，从而揭示了其作为治疗靶点的潜力。
Staufen1 interacts with mRNAs with expanded CUG repeats and promotes their nuclear export and translation, while also promoting alternative splicing of other mRNAs. In myotonic dystrophy type 1 (DM1), dystrophia myotonica protein kinase messenger ribonucleic acids (RNAs; mRNAs) with expanded CUG repeats (CUGexp) aggregate in the nucleus and become toxic to cells by sequestering and/or misregulating RNA-binding proteins, resulting in aberrant alternative splicing. In this paper, we find that the RNA-binding protein Staufen1 is markedly and specifically increased in skeletal muscle from DM1 mouse models and patients. We show that Staufen1 interacts with mutant CUGexp mRNAs and promotes their nuclear export and translation. This effect is critically dependent on the third double-stranded RNA–binding domain of Staufen1 and shuttling of Staufen1 into the nucleus via its nuclear localization signal. Moreover, we uncover a new role of Staufen1 in splicing regulation. Overexpression of Staufen1 rescues alternative splicing of two key pre-mRNAs known to be aberrantly spliced in DM1, suggesting its increased expression represents an adaptive response to the pathology. Altogether, our results unravel a novel function for Staufen1 in splicing regulation and indicate that it may positively modulate the complex DM1 phenotype, thereby revealing its potential as a therapeutic target.
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