Article abstract
Nature Cell Biology 9, 379 - 390 (2007)
Published online: 18 March 2007 | doi:10.1038/ncb1554
There is an Addendum (May 2007) associated with this Article.
The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy
Philipp Christoph Janiesch1,4, Johnny Kim1,4, Julien Mouysset1, Roja Barikbin1, Hanns Lochmüller2, Giuseppe Cassata3, Sabine Krause2 & Thorsten Hoppe1
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.
- Centre for Molecular Neurobiology (ZMNH), University of Hamburg, Falkenried 94, 20251 Hamburg, Germany.
- Friedrich-Baur-Institute and Department of Neurology, Ludwig Maximilians University, Marchioninistr. 17, 81377 Munich, Germany.
- IFOM-FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milano, Italy.
- These authors contributed equally to this work.
Correspondence to: Thorsten Hoppe1 e-mail: thorsten.hoppe@zmnh.uni-hamburg.de
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