Philipp Christoph Janiesch et al. (2008) European Worm Meeting "The Ubiquitin-Selective Chaperone CDC-48 Links Myosin Assembly in C. elegans to Human Myopathy"

Hanns Lochmuller, Thorsten Hoppe,, Philipp Christoph Janiesch, Giuseppe Cassata, Roja Barikbin, Johnny Kim, Sabine Krause, Julien Mouysset

[European Worm Meeting, 2008]

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 are still unclear. Here, we discovered an unanticipated function. of CDC-48/p97 in myosin assembly and myofibril organization both in C.. 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 man. 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 of CDC-. 48/p97 in the process of myofiber differentiation and maintenance, which is. abolished during pathological conditions leading to protein aggregation and. inclusion body formation in human skeletal muscle. To our knowledge this is. the first study implicating functional myosin assembly and maintenance in. the pathophysiology of human inclusion body myopathy associated with Paget. disease of bone and frontotemporal dementia (IBMPFD).. The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human. myopathy. Janiesch P.C., Kim J., Mouysset J., Barikbin R., Lochmuller H.,. Cassata G., Krause S., and Hoppe T. (2007). Nat. Cell Biol. 9, 379-390.. Multiubiquitylation by E4 enzymes: one size doesn''t fit all.. Hoppe T. (2005). Trends Biochem. Sci. 30, 183-187.

Philipp Christoph Janiesch et al. (2008) European Worm Meeting "The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy"

Julien Mouysset, Thorsten Hoppe, Roja Barikbin, Sabine Krause, Giuseppe Cassata, Hanns Lochmuller, Philipp Christoph Janiesch, Johnny Kim

[European Worm Meeting, 2008]

Development and regeneration of skeletal muscle is a highly ordered and. dynamic process that depends on proper sarcomere organization during the. myogenic process. Recent data have identified the ubiquitin proteasome. system (UPS) to play a key role not only in the maintenance of the. sarcomere but also during regeneration and development of striated muscle.. Accordingly, ubiquitin-dependent protein degradation is known to occur. prominently in muscle cells, both in physiologic and disease states.. p97 (also known as CDC-48 in C. elegans) is an ubiquitin-selective. chaperone that is involved in substrate recruitment and ubiquitin chain. assembly. However, the physiological relevance of p97 and its role in. developmental processes have remained unclear. Here, we discovered an. unanticipated novel role of CDC-48/p97 in myosin assembly and myofibril. organization both in C. elegans and humans. We revealed the developmentally. regulated assembly of a trimeric complex - consisting of CDC-48 and the. ubiquitin ligases UFD-2 and CHN-1 - which links turnover of the myosin-. directed chaperone UNC-45 to functional muscle formation. Our data suggest. a similarly conserved pathway regulating myosin assembly in man.. Remarkably, mutations in human p97 known to cause hereditary inclusion body. myopathy abrogate this muscle-specific activity and result in severely. disorganized myofibrils, detrimental towards sarcomeric function. These. results identify a key role of CDC-48/p97 in the process of myofiber. differentiation and maintenance, which is abolished during pathological. conditions leading to protein aggregation and inclusion body formation in. human skeletal muscle.. Hoppe T. et al. (2004).. Regulation of the Myosin-Directed Chaperone UNC-45 by a Novel E3/E4-. Multiubiquitylation Complex in C. elegans. Cell 118, 337-49.. Hoppe T. (2005).. Multiubiquitylation by E4 enzymes: one size doesn''t fit all. Trends. Biochem. Sci. 30, 183-187.. Janiesch et al. (2007).. The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human. myopathy. Nat Cell Biol. 4, 379-90.. Do not add objects such as pictures, boxes, headers, footers, footnotes,. etc.