Cullin-3 dependent deregulation of ACTN1 represents a pathogenic mechanism in nemaline myopathy
Cullin-3 dependent deregulation of ACTN1 represents a pathogenic mechanism in nemaline myopathy
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DOI：
10.1172/jci.insight.125665
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发表时间：
2019-05-16
期刊：
影响因子：
8
通讯作者：
Lange, Stephan
中科院分区：
文献类型：
--
作者：
Blondelle, Jordan;Tallapaka, Kavya;Lange, Stephan
线状肌病是一种先天性神经肌肉疾病，以肌肉无力、纤维萎缩和肌纤维内线状小体的存在为特征。然而，对潜在的致病机制缺乏了解。最近，E3泛素连接酶cullin-3的三个底物接头KBTBD13、KLHL40和KLHL41的突变与早发性线虫肌病有关。我们假设，cullin-3及其肌肉蛋白底物的放松调控可能是疾病发展的原因。使用cullin-3基因敲除小鼠，我们发现非肌肉α-肌动蛋白(ACTN1和ACTN4)在这些小鼠的肌肉中积累，我们在KBTBD13突变的患者中也观察到了这一点。我们的数据显示，对cullin-3活性和ACTN1水平的适当调节对于正常的肌肉和神经肌肉连接发育是必不可少的。虽然ACTN1在肌肉发生过程中自然下调，但它在C2C12成肌细胞中的过度表达引发了融合、肌肉发生和乙酰胆碱受体聚集方面的缺陷-我们在cullin-3缺陷小鼠中描述了这些特征。综上所述，我们的数据强调了cullin-3介导的ACTN1降解对肌肉发育的重要性，并表明了我们所知的在cullin-3基因敲除小鼠和线虫肌病患者中看到的肌肉病的病因学的新的病理机制。
Nemaline myopathy is a congenital neuromuscular disorder characterized by muscle weakness, fiber atrophy, and presence of nemaline bodies within myofibers. However, understanding of the underlying pathomechanisms is lacking. Recently, mutations in KBTBD13, KLHL40, and KLHL41, three substrate adaptors for the E3 ubiquitin ligase Cullin-3, have been associated with early-onset nemaline myopathies. We hypothesized that deregulation of Cullin-3 and its muscle protein substrates may be responsible for disease development. Using Cullin-3-knockout mice, we identified accumulation of non-muscle alpha-actinins (ACTN1 and ACTN4) in muscles of these mice, which we also observed in patients with mutations in KBTBD13. Our data reveal that proper regulation of Cullin-3 activity and ACTN1 levels is essential for normal muscle and neuromuscular junction development. While ACTN1 is naturally downregulated during myogenesis, its overexpression in C2C12 myoblasts triggered defects in fusion, myogenesis, and acetylcholine receptor clustering - features that we characterized in Cullin-3-deficient mice. Taken together, our data highlight the importance of Cullin-3-mediated degradation of ACTN1 for muscle development, and indicate what is to our knowledge new pathomechanism for the etiology of myopathies seen in Cullin-3-knockout mice and patients with nemaline myopathy.