A mutation in CHN-1/CHIP suppresses muscle degeneration in Caenorhabditis elegans.
Duchenne muscular dystrophy (DMD) is one of the most severe X-linked, inherited diseases of childhood, characterized by progressive muscle wasting and weakness as the consequence of mutations in the dystrophin gene. The protein encoded by dystrophin is a huge cytosolic protein that links the intracellular F-actin filaments to the members of the dystrophin-glycoprotein-complex (DGC). Dystrophin deficiency results in the absence or reduction of complex components that are degraded through an unknown pathway. We show here that muscle degeneration in a Caenorhabditis elegans DMD model is efficiently reduced by downregulation of chn-1, encoding the homologue of the human E3/E4 ubiquitylation enzyme CHIP. A deletion mutant of chn-1 delays the cell death of body-wall muscle cells and improves the motility of animals carrying mutations in dystrophin and MyoD. Elimination of chn-1 function in the musculature, but not in the nervous system, is sufficient for this effect, and can be phenocopied by proteasome inhibitor treatment. This suggests a critical role of CHIP/CHN-1-mediated ubiquitylation in the control of muscle wasting and degeneration and identifies a potential new drug target for the treatment of this disease.
Nyamsuren
Oyunbileg
O
Bio 3, Bioinformatics and Molecular Genetics (Faculty of Biology), Schaenzlestr. 1, D-79104 Freiburg, Germany.
Faggionato
Davide
D
Loch
Wiebke
W
Schulze
Ekkehard
E
Baumeister
Ralf
R
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics*; D002452:Cell Count; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D017238:Genes, Helminth; D007976:Leupeptins / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects; D009137:Muscular Dystrophy, Animal / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009218:Myosins / Q000378:metabolism; D010590:Phalloidine; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D029742:Caenorhabditis elegans Proteins; D007976:Leupeptins; D010590:Phalloidine; D044767:Ubiquitin-Protein Ligases; C487100:chn-1 protein, C elegans; D009218:Myosins; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde