RRC ID 4173
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.
Abstract 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.
Volume 9(4)
Pages 379-90
Published 2007-4
DOI 10.1038/ncb1554
PII ncb1554
PMID 17369820
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
IF 17.728
Times Cited 90
C.elegans tm1380 tm544 tm659 tm1359 tm1349