The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy

Nat Cell Biol. 2007 Apr;9(4):379-90. doi: 10.1038/ncb1554. Epub 2007 Mar 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Caenorhabditis elegans Proteins
  • Cell Cycle Proteins
  • Molecular Chaperones
  • Nuclear Proteins
  • Ubiquitin
  • Green Fluorescent Proteins
  • Adenosine Triphosphatases
  • p97 ATPase
  • Myosins
  • Valosin Containing Protein