Proteasome function is required to maintain muscle cellular architecture
Proteasome function is required to maintain muscle cellular architecture
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DOI：
10.1042/bc20070019
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发表时间：
2007-11-01
影响因子：
2.7
通讯作者：
Broadie, Kendal
中科院分区：
文献类型：
--
作者：
Haas, Kevin F.;Woodruff, Elvin;Broadie, Kendal
背景资料。通过UPS(泛素-蛋白酶体系统)的蛋白质降解在肌肉代谢和信号通路中起着关键作用。本研究使用突变的蛋白酶体β亚基的条件表达来研究肌肉中UPS的时间需求，以导致蛋白酶体功能的靶向抑制。结果与结论。使用了果蝇GeneSwitch系统，分析了具有良好特征的幼体体壁肌肉。这种方法严重扰乱了蛋白酶体的功能，并导致多泛素化蛋白的快速积累，特别是在肌肉中。在转基因蛋白酶体抑制的12h内，肌肉结构明显紊乱，肌肉萎缩明显，直至停止所有协调运动。进行性肌肉结构变化包括肌节组织迅速丧失，核间距/图案丧失，空泡形成，超微结构水平核质聚集体聚集。在神经肌肉交界处，突触下网高度专门化的肌膜折叠迅速消失。在转基因蛋白酶体被抑制后的24 h内，肌肉中含有大量的自噬小体，内质网伴侣蛋白GRP78(78 kDa的葡萄糖调节蛋白)的表达显著增加，表明肌肉维持的丧失与未折叠蛋白反应的诱导有关。综上所述，这些结果表明，UPS是维持肌肉和神经肌肉连接结构的迫切需要，并提供了一个果蝇遗传模型来从机械上评估这一要求。
Background information. Protein degradation via the UPS (ubiquitin-proteasome system) plays critical roles in muscle metabolism and signalling pathways. The present study investigates temporal requirements of the UPS in muscle using conditional expression of mutant proteasome beta subunits to cause targeted inhibition of proteasome function.Results and conclusions. The Drosophila GeneSwitch system was used, with analyses of the well-characterized larval somatic body wall muscles. This method acutely disrupts proteasome function and causes rapid accumulation of polyubiquitinated proteins, specifically within the muscle. Within 12 h of transgenic proteasome inhibition, there was a gross disorganization of muscle architecture and prominent muscle atrophy, progressing to the arrest of all co-ordinated movement by 24 h. Progressive muscle architecture changes include rapid loss of sarcomere organization, loss of nuclei spacing/patterning, vacuole formation and the accumulation of nuclear and cytoplasmic aggregates at the ultrastructural level. At the neuromuscular junction, the highly specialized muscle membrane folds of the subsynaptic reticulum were rapidly lost. Within 24 h after transgenic proteasome inhibition, muscles contained numerous autophagosomes and displayed highly elevated expression of the endoplasmic reticulum chaperone GRP78 (glucose-regulated protein of 78 kDa), indicating that the loss of muscle maintenance correlates with induction of the unfolded protein response. Taken together, these results demonstrate that the UPS is acutely required for maintenance of muscle and neuromuscular junction architecture, and provides a Drosophila genetic model to mechanistically evaluate this requirement.