The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy
The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy
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DOI：
10.1038/ncb1554
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发表时间：
2007-04-01
影响因子：
21.3
通讯作者：
Hoppe, Thorsten
中科院分区：
文献类型：
--
作者：
Janiesch, Philipp Christoph;Kim, Johnny;Hoppe, Thorsten
真核生物中的蛋白质降解通常需要泛素选择性伴侣蛋白p97来招募底物和组装泛素链。然而，p97的生理相关性及其在发育过程中的作用尚不清楚。在这里，我们发现了CDC-48/p97在秀丽隐杆线虫和人类中肌球蛋白组装和肌原纤维组织中的一个意想不到的功能。发育调节的CDC-48 -UFD-2 -CHN-1复合体的组装将肌球蛋白导向的伴侣UNC-45的周转与功能性肌肉形成联系起来。我们的数据表明，在人类中有类似的保守途径调节肌球蛋白的组装。值得注意的是，已知会导致遗传性包涵体肌病的人类p97突变会破坏UNC-45的降解，并导致肌原纤维严重紊乱，对肌肉功能有害。这些结果确定了CDC-48/p97在肌纤维分化和维持过程中的关键作用，该过程在导致人类骨骼肌蛋白质聚集和包涵体形成的病理条件下被取消。
Protein degradation in eukaryotes often requires the ubiquitin-selective chaperone p97 for substrate recruitment and ubiquitin-chain assembly. However, the physiological relevance of p97, and its role in developmental processes, remain unclear. Here, we discover an unanticipated function for CDC-48/p97 in myosin assembly and myofibril organization, both in Caenorhabditis elegans and humans. The developmentally regulated assembly of a CDC-48 -UFD-2 -CHN-1 complex links turnover of the myosin-directed chaperone UNC-45 to functional muscle formation. Our data suggest a similarly conserved pathway regulating myosin assembly in humans. Remarkably, mutations in human p97, known to cause hereditary inclusion-body myopathy, abrogate UNC-45 degradation and result in severely disorganized myofibrils, detrimental towards sarcomeric function. These results identify a key role for CDC-48/p97 in the process of myofibre differentiation and maintenance, which is abolished during pathological conditions leading to protein aggregation and inclusion-body formation in human skeletal muscle.