Nuclear poly(A) binding protein 1 (PABPN1) and Matrin3 interact in muscle cells and regulate RNA processing.
Nuclear poly(A) binding protein 1 (PABPN1) and Matrin3 interact in muscle cells and regulate RNA processing.
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DOI：
10.1093/nar/gkx786
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发表时间：
2017-10-13
影响因子：
14.9
通讯作者：
Corbett AH
中科院分区：
文献类型：
--
作者：
Banerjee A;Vest KE;Pavlath GK;Corbett AH
多聚腺苷结合蛋白1(PABPN1)是一种广泛表达的RNA结合蛋白，在RNA代谢的多个步骤中起重要作用。虽然PABPN1在RNA加工的调节中起着关键作用，但编码这种普遍表达的RNA结合蛋白的基因突变会导致一种特殊形式的肌营养不良症，称为眼咽肌营养不良症(OPMD)。尽管在这种疾病中发生了组织特异性的病理，但直到最近，对PABPN1的研究才开始探索这种蛋白在骨骼肌中的作用。我们使用免疫共沉淀和质谱仪来鉴定小鼠骨骼肌中与PABPN1相互作用的蛋白质。在相互作用的蛋白质中，我们确定Matrin 3(MATR3)是PABPN1的一个新的蛋白质相互作用元件。MATR3基因在远端肌病和肌萎缩侧索硬化症(ALS)中发生突变。我们证明，与PABPN1一样，MATR3对肌肉发生也是至关重要的。此外，MATR3控制RNA加工的关键方面，包括交替的多聚腺苷基化和内含子保留。我们提供的证据表明，MATR3还结合和调节长非编码RNA(LncRNA)Neat1的水平，并且与PABPN1一起是正常的副斑点功能所必需的。我们证明了PABPN1和MATR3是副蛋白以及腺苷到肌苷(A到I)RNA编辑肌肉细胞中CTN RNA所必需的。我们通过调节一个常见的lncRNA靶来提供PABPN1和MATR3之间的功能联系，并对副斑点的形态和功能产生下游影响。我们将我们的分析扩展到OPMD的小鼠模型，并展示了在存在内源性水平的丙氨酸扩展的PABPN1时，副斑点形态发生了变化。在本研究中，我们报道了PABPN1的蛋白结合伙伴，这有助于深入了解PABPN1在骨骼肌中的新功能，并识别在OPMD中发现的核聚集体中可以与丙氨酸扩展的PABPN1隔离的蛋白质。
The polyadenylate binding protein 1 (PABPN1) is a ubiquitously expressed RNA binding protein vital for multiple steps in RNA metabolism. Although PABPN1 plays a critical role in the regulation of RNA processing, mutation of the gene encoding this ubiquitously expressed RNA binding protein causes a specific form of muscular dystrophy termed oculopharyngeal muscular dystrophy (OPMD). Despite the tissue-specific pathology that occurs in this disease, only recently have studies of PABPN1 begun to explore the role of this protein in skeletal muscle. We have used co-immunoprecipitation and mass spectrometry to identify proteins that interact with PABPN1 in mouse skeletal muscles. Among the interacting proteins we identified Matrin 3 (MATR3) as a novel protein interactor of PABPN1. The MATR3 gene is mutated in a form of distal myopathy and amyotrophic lateral sclerosis (ALS). We demonstrate, that like PABPN1, MATR3 is critical for myogenesis. Furthermore, MATR3 controls critical aspects of RNA processing including alternative polyadenylation and intron retention. We provide evidence that MATR3 also binds and regulates the levels of long non-coding RNA (lncRNA) Neat1 and together with PABPN1 is required for normal paraspeckle function. We demonstrate that PABPN1 and MATR3 are required for paraspeckles, as well as for adenosine to inosine (A to I) RNA editing of Ctn RNA in muscle cells. We provide a functional link between PABPN1 and MATR3 through regulation of a common lncRNA target with downstream impact on paraspeckle morphology and function. We extend our analysis to a mouse model of OPMD and demonstrate altered paraspeckle morphology in the presence of endogenous levels of alanine-expanded PABPN1. In this study, we report protein-binding partners of PABPN1, which could provide insight into novel functions of PABPN1 in skeletal muscle and identify proteins that could be sequestered with alanine-expanded PABPN1 in the nuclear aggregates found in OPMD.
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影响因子：
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