Lafora disease ubiquitin ligase malin promotes proteasomal degradation of neuronatin and regulates glycogen synthesis
Lafora disease ubiquitin ligase malin promotes proteasomal degradation of neuronatin and regulates glycogen synthesis
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DOI：
10.1016/j.nbd.2011.06.013
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发表时间：
2011-10-01
影响因子：
6.1
通讯作者：
Jana, Nihar Ranjan
中科院分区：
文献类型：
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作者：
Sharma, Jaiprakash;Rao, Sudheendra N. R.;Jana, Nihar Ranjan
Lafora病（LD）是一种遗传性进行性肌阵挛癫痫，由编码蛋白磷酸酶laforin的EPM2A基因或编码泛素连接酶malin的NHLRC 1基因突变引起。由于malin是一种泛素连接酶，其突变导致LD，因此推测其底物的不适当清除可能导致LD发病。在这里，我们首次证明，neuronatin是一种新的底物的malin。Malin与neuronatin相互作用并通过蛋白酶体促进其降解。有趣的是，neuronatin是一种易于聚集的蛋白质，在抑制细胞蛋白酶体功能时形成侵袭体，并将malin募集到这些侵袭体中。发现神经元素通过激活糖原合成酶来刺激糖原合成，而马林可阻止神经元素诱导的糖原合成。马林蛋白的几种LD相关突变体在神经素的降解和神经素诱导的糖原合成的抑制中是无效的。最后，我们证明了LD患者皮肤活检样本中神经元素水平的增加。总体而言，我们的研究结果表明，malin负调控neuronatin和它的功能丧失在LD的结果增加的积累，这可能涉及Lafora体的形成或其他方面的疾病发病机制。(C)2011 Elsevier Inc. All rights reserved.
Lafora disease (LD) is the inherited progressive myoclonus epilepsy caused by mutations in either EPM2A gene, encoding the protein phosphatase laforin or the NHLRC1 gene, encoding the ubiquitin ligase malin. Since malin is an ubiquitin ligase and its mutations cause LD, it is hypothesized that improper clearance of its substrates might lead to LD pathogenesis. Here, we demonstrate for the first time that neuronatin is a novel substrate of malin. Malin interacts with neuronatin and enhances its degradation through proteasome. Interestingly, neuronatin is an aggregate prone protein, forms aggresome upon inhibition of cellular proteasome function and malin recruited to those aggresomes. Neuronatin is found to stimulate the glycogen synthesis through the activation of glycogen synthase and malin prevents neuronatin-induced glycogen synthesis. Several LD-associated mutants of malin are ineffective in the degradation of neuronatin and suppression of neuronatin-induced glycogen synthesis. Finally, we demonstrate the increased levels of neuronatin in the skin biopsy sample of LD patients. Overall, our results indicate that malin negatively regulates neuronatin and its loss of function in LD results in increased accumulation of neuronatin, which might be implicated in the formation of Lafora body or other aspect of disease pathogenesis. (C) 2011 Elsevier Inc. All rights reserved.