The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy.
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The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy. / Janiesch, Phillipp Christoph; Kim, Johnny; Mouysset, Julien; Barikbin, Roja; Lochmüller, Hanns; Cassata, Giuseppe; Krause, Sabine; Hoppe, Thorsten.
In: NAT CELL BIOL, Vol. 9, No. 4, 4, 2007, p. 379-390.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy.
AU - Janiesch, Phillipp Christoph
AU - Kim, Johnny
AU - Mouysset, Julien
AU - Barikbin, Roja
AU - Lochmüller, Hanns
AU - Cassata, Giuseppe
AU - Krause, Sabine
AU - Hoppe, Thorsten
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 9
SP - 379
EP - 390
JO - NAT CELL BIOL
JF - NAT CELL BIOL
SN - 1465-7392
IS - 4
M1 - 4
ER -
