Control of mRNA stability contributes to low levels of nuclear poly(A) binding protein 1 (PABPN1) in skeletal muscle.
Control of mRNA stability contributes to low levels of nuclear poly(A) binding protein 1 (PABPN1) in skeletal muscle.
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DOI：
10.1186/2044-5040-3-23
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发表时间：
2013-10-01
期刊：
影响因子：
4.9
通讯作者：
Pavlath GK
中科院分区：
文献类型：
--
作者：
Apponi LH;Corbett AH;Pavlath GK
核多聚腺苷酸结合蛋白1（PABPN1）是一种广泛表达的蛋白质，在基因表达的转录后调控的多个步骤中发挥关键作用。PABPN1 N端多聚丙氨酸束的短暂扩张导致眼咽肌营养不良症（OPMD），这是一种成人发病疾病，其特征在于眼睑下垂、吞咽困难和近端肢体肌肉无力。丙氨酸扩增的PABPN1导致肌肉特异性病理的原因尚不清楚。鉴于PABPN1在RNA代谢中的一般功能，骨骼肌的固有特性可能使该组织对突变PABPN1的作用敏感。为了开始了解OPMD的肌肉特异性，我们研究了人和小鼠不同组织中PABPN1的稳态水平。此外，我们分析了小鼠损伤后肌肉再生过程中PABPN1的水平。此外，我们评估了与肾脏相比，骨骼肌中PABPN1 mRNA衰减的动力学。在这里，我们表明，与其他组织相比，小鼠和人类骨骼肌中PABPN1 mRNA和蛋白的稳态水平显著降低，特别是那些受OPMD影响的骨骼肌。相比之下，PABPN1水平在肌肉再生过程中增加，表明组织修复过程中对PABPN1功能的需求更大。进一步的分析表明PABPN1表达的调节可能是由于在mRNA稳定性水平上起作用的转录后机制。我们的研究结果表明，PABPN1稳态水平和可能的表达控制在骨骼肌中与其他组织相比存在显著差异，这可能对理解OPMD的肌肉特异性具有重要意义。
The nuclear poly(A) binding protein 1 (PABPN1) is a ubiquitously expressed protein that plays critical roles at multiple steps in post-transcriptional regulation of gene expression. Short expansions of the polyalanine tract in the N-terminus of PABPN1 lead to oculopharyngeal muscular dystrophy (OPMD), which is an adult onset disease characterized by eyelid drooping, difficulty in swallowing, and weakness in the proximal limb muscles. Why alanine-expanded PABPN1 leads to muscle-specific pathology is unknown. Given the general function of PABPN1 in RNA metabolism, intrinsic characteristics of skeletal muscle may make this tissue susceptible to the effects of mutant PABPN1. To begin to understand the muscle specificity of OPMD, we investigated the steady-state levels of PABPN1 in different tissues of humans and mice. Additionally, we analyzed the levels of PABPN1 during muscle regeneration after injury in mice. Furthermore, we assessed the dynamics of PABPN1 mRNA decay in skeletal muscle compared to kidney. Here, we show that the steady-state levels of both PABPN1 mRNA and protein are drastically lower in mouse and human skeletal muscle, particularly those impacted in OPMD, compared to other tissues. In contrast, PABPN1 levels are increased during muscle regeneration, suggesting a greater requirement for PABPN1 function during tissue repair. Further analysis indicates that modulation of PABPN1 expression is likely due to post-transcriptional mechanisms acting at the level of mRNA stability. Our results demonstrate that PABPN1 steady-state levels and likely control of expression differ significantly in skeletal muscle as compared to other tissues, which could have important implications for understanding the muscle-specific nature of OPMD.
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影响因子：
5.5
作者：
Bondesen, BA;Mills, ST;Pavlath, GK
通讯作者：
Pavlath, GK
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WAHLE, E
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