The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy.
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.
Janiesch
Philipp Christoph
PC
Centre for Molecular Neurobiology (ZMNH), University of Hamburg, Falkenried 94, 20251 Hamburg, Germany.
Kim
Johnny
J
Mouysset
Julien
J
Barikbin
Roja
R
Lochmüller
Hanns
H
Cassata
Giuseppe
G
Krause
Sabine
S
Hoppe
Thorsten
T
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009135:Muscular Diseases / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009218:Myosins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D014162:Transfection; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism*; D000074405:Valosin Containing Protein
D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D000251:Adenosine Triphosphatases; C404942:p97 ATPase; D009218:Myosins; D000074405:Valosin Containing Protein