Reference - Detail
|Author||Janiesch PC, Kim J, Mouysset J, Barikbin R, Lochmüller H, Cassata G, Krause S, Hoppe T.|
|Title||The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy.|
|Journal||Nat. Cell Biol.|
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.
|MeSH||Adenosine Triphosphatases / genetics Adenosine Triphosphatases / metabolism* Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cell Cycle Proteins / genetics Cell Cycle Proteins / metabolism* Cell Line Cells, Cultured Fluorescent Antibody Technique Green Fluorescent Proteins / genetics Green Fluorescent Proteins / metabolism Humans Molecular Chaperones / genetics Molecular Chaperones / metabolism Muscle Fibers, Skeletal / metabolism Muscular Diseases / metabolism* Muscular Diseases / pathology Mutation Myosins / genetics Myosins / metabolism* Nuclear Proteins / genetics Nuclear Proteins / metabolism* Protein Binding RNA Interference Transfection Two-Hybrid System Techniques Ubiquitin / metabolism* Valosin Containing Protein|
|WOS Category||CELL BIOLOGY|
|C.elegans||tm1380 tm544 tm659 tm1359 tm1349|