Muscleblind-Like 1 and Muscleblind-Like 3 Depletion Synergistically Enhances Myotonia by Altering Clc-1 RNA Translation
Muscleblind-Like 1 and Muscleblind-Like 3 Depletion Synergistically Enhances Myotonia by Altering Clc-1 RNA Translation
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DOI：
10.1016/j.ebiom.2015.07.028
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发表时间：
2015-09-01
期刊：
影响因子：
11.1
通讯作者：
Reddy, Sita
中科院分区：
文献类型：
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作者：
Choi, Jongkyu;Personius, Kirkwood E.;Reddy, Sita
已知肌盲样1 （Mbnl1）的缺失会改变Clc-1剪接从而导致肌强直。Mbnl1(Delta E3/Delta E3)/Mbnl3（Delta E2）小鼠，在Mbnl1和Mbnl3缺失的情况下，在非常低的Clc-1电流下，肌肉强直和肌纤维数量明显增强，其中gCl（max）值接近1 mS/cm(2)，而Clc-1剪接错误、多聚a位点选择或Clc-1定位的改变没有进一步增强。值得注意的是，Mbnl1(Delta E3/Delta E3)/Mbnl3（Delta E2）肌肉显示出Clc-1 RNA单体和第一多体上的异常积累。Mbnl1和Mbnl3结合Clc-1 RNA，这两种蛋白都结合Hsp70和eEF1A，在RNA存在下，这些关联减弱。因此，Mbnl1和Mbnl3与核糖体结合的Clc-1 mRNA结合，可以促进Hsp70和eEF1A局部浓度的增加，从而帮助Clc-1翻译。因此，Mbnl1和Mbnl3的双重缺失会引发Clc-1剪接错误和翻译缺陷，从而协同增强肌强直。由于肌强直性营养不良（DM1）的HSA（LR）模型显示出类似的Clc-1缺陷，本研究表明DM1病理表现需要剪接错误和翻译缺陷。背景研究：1型肌强直性营养不良（DM1）是一种显性疾病，由扩展的CUG重复RNA表达引起，该RNA异常地隔离和失活了肌盲样（MBNL）蛋白家族。在小鼠中，已知Mbnl1的失活会改变Clc-1剪接，导致肌强直。我们证明Mbnl1和Mbnl3的同时消耗导致肌强直的协同增强，肌肉纤维的增加显示出低氯电流。所观察到的协同作用是由于Clc-1 mRNA在单体和第一多体上的异常积累。这种翻译错误反映了Mbnl1和Mbnl3作为接头的能力，将Hsp70和eEF1A招募到与核糖体结合的Clc-1 mRNA上，以促进翻译。因此，我们的研究表明，在缺乏Mbnl1和Mbnl3的小鼠中，Clc-1 RNA翻译缺陷与Clc-1剪接错误协同作用，协同增强肌强直。(C) 2015年作者。这是一篇基于CC by-nc-nd许可（http://creativecommons.org/licenses/by-nc-nd/4.0/）的开放获取文章。
Loss of Muscleblind-like 1 (Mbnl1) is known to alter Clc-1 splicing to result in myotonia. Mbnl1(Delta E3/Delta E3)/Mbnl3(Delta E2) mice, depleted of Mbnl1 and Mbnl3, demonstrate a profound enhancement of myotonia and an increase in the number of muscle fibers with very low Clc-1 currents, where gCl(max) values approach similar to 1 mS/cm(2), with the absence of a further enhancement in Clc-1 splice errors, alterations in polyA site selection or Clc-1 localization. Significantly, Mbnl1(Delta E3/Delta E3)/Mbnl3(Delta E2) muscles demonstrate an aberrant accumulation of Clc-1 RNA onmonosomes and on the first polysomes. Mbnl1 and Mbnl3 bind Clc-1 RNA and both proteins bind Hsp70 and eEF1A, with these associations being reduced in the presence of RNA. Thus binding of Mbnl1 and Mbnl3 to Clc-1 mRNA engaged with ribosomes can facilitate an increase in the local concentration of Hsp70 and eEF1A to assist Clc-1 translation. Dual depletion of Mbnl1 and Mbnl3 therefore initiates both Clc-1 splice errors and translation defects to synergistically enhance myotonia. As the HSA(LR) model for myotonic dystrophy (DM1) shows similar Clc-1 defects, this study demonstrates that both splice errors and translation defects are required for DM1 pathology to manifest.Research in context: Research in context: Myotonic Dystrophy type 1 (DM1) is a dominant disorder resulting from the expression of expanded CUG repeat RNA, which aberrantly sequesters and inactivates the muscleblind-like (MBNL) family of proteins. In mice, inactivation of Mbnl1 is known to alter Clc-1 splicing to result in myotonia. We demonstrate that concurrent depletion of Mbnl1 and Mbnl3 results in a synergistic enhancement of myotonia, with an increase in muscle fibers showing low chloride currents. The observed synergism results from the aberrant accumulation of Clc-1 mRNA on monosomes and the first polysomes. This translation error reflects the ability of Mbnl1 and Mbnl3 to act as adaptors that recruit Hsp70 and eEF1A to the Clc-1 mRNA engaged with ribosomes, to facilitate translation. Thus our study demonstrates that Clc-1 RNA translation defects work coordinately with Clc-1 splice errors to synergistically enhance myotonia in mice lacking Mbnl1 and Mbnl3. (C) 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).