Reduction of the rate of protein translation in patients with myotonic dystrophy 2.
Reduction of the rate of protein translation in patients with myotonic dystrophy 2.
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DOI：
10.1523/jneurosci.1983-09.2009
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发表时间：
2009-07-15
期刊：
影响因子：
--
通讯作者：
Timchenko L
中科院分区：
文献类型：
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作者：
Huichalaf C;Schoser B;Schneider-Gold C;Jin B;Sarkar P;Timchenko L
强直性肌营养不良症2(DM2)是一种常染色体显性遗传性多系统疾病，主要累及骨骼肌。DM2是由ZNF9基因内含子1的CCTGn扩增引起的。突变CCUGn RNA的表达改变了DM2患者的RNA加工；然而，ZNF9蛋白在DM2病理中的作用尚未阐明。ZNF9已被证明调节大写字母依赖和大写字母非依赖的翻译。我们研究了ZNF9在DM2患者翻译调节中的可能作用。我们已经发现ZNF9与编码人核糖体蛋白RPS17、聚(A)结合蛋白PABP1以及延伸因子eEF1A和eEF2的5‘UTRs相互作用。在DM2肌肉中，ZNF9与这些顶端含5‘UTRs的结合活性降低。随着这种活性的降低，DM2肌肉中RPS17、PABP、eEF1a和eEF2蛋白的水平也降低了。DM2中ZNF9 RNA结合活性的降低与其胞浆中ZNF9蛋白水平的降低有关。我们发现ZNF9的减少是由突变的CCUG重复序列的表达引起的。DM2中翻译机构蛋白质的减少与DM2患者成肌细胞蛋白质合成速度的降低有关。我们发现，ZNF9在DM2成肌细胞中的异位表达纠正了蛋白质合成的速度，这表明CCUG-ZNF9-TOP mRNAs通路的改变是导致DM2肌细胞蛋白质翻译速度降低的原因。
Myotonic Dystrophy 2 (DM2) is an autosomal dominant, multisystem disease, which primarily affects skeletal muscle. DM2 is caused by CCTGn expansion in the intron 1 of the ZNF9 gene. Expression of the mutant CCUGn RNA changes RNA processing in patients with DM2; however, the role of ZNF9 protein in DM2 pathology has been not elucidated. ZNF9 has been shown to regulate cap-dependent and cap-independent translation. We have examined a possible role of ZNF9 in the regulation of translation in DM2 patients. We have found that ZNF9 interacts with the 5′ UTRs of TOP (terminal oligopyrimidine tract) mRNAs encoding human ribosomal protein, RPS17, poly(A)-binding protein, PABP1, and elongation factors, eEF1A and eEF2. The binding activity of ZNF9 toward these TOP-containing 5′ UTRs is reduced in DM2 muscle. Consistent with the reduction of this activity, the levels of RPS17, PABP, eEF1A and eEF2 proteins are also diminished in DM2 muscle. The reduction of ZNF9 RNA-binding activity in DM2 correlates with a decrease of ZNF9 protein levels in cytoplasm of DM2 muscle cells. We have found that the reduction of ZNF9 is caused by expression of the mutant CCUG repeats. This decrease of proteins of translational apparatus in DM2 correlates with a reduction of a rate of protein synthesis in myoblasts from DM2 patients. We found that the ectopic expression of ZNF9 in DM2 myoblasts corrects rate of protein synthesis suggesting that the alterations in CCUG-ZNF9-TOP mRNAs pathway are responsible for the reduction of the rate of protein translation in DM2 muscle cells.