Key result
Overexpression of UNC-45 in C. elegans leads to decreased myosin content and mild paralysis via ubiquitin/proteasome degradation, which is restored by partial proteasome inhibition.
UNC-45 overexpression leads to myosin degradation via the ubiquitin/proteasome system, suggesting a potential mechanism for muscle wasting in conditions like heart failure.
May implicate UNC-45 in myosin loss during heart failure cachexia; leaves open proteasome modulation as therapy.
Myosin motors are central to diverse cellular processes in eukaryotes. Homologues of the myosin chaperone UNC-45 have been implicated in the assembly and function of myosin-containing structures in organisms from fungi to humans. In muscle, the assembly of sarcomeric myosin is regulated to produce stable, uniform thick filaments. Loss-of-function mutations in Caenorhabditis elegans UNC-45 lead to decreased muscle myosin accumulation and defective thick filament assembly, resulting in paralyzed animals. We report that transgenic worms overexpressing UNC-45 also display defects in myosin assembly, with decreased myosin content and a mild paralysis phenotype. We find that the reduced myosin accumulation is the result of degradation through the ubiquitin/proteasome system. Partial proteasome inhibition is able to restore myosin protein and worm motility to nearly wild-type levels. These findings suggest a mechanism in which UNC-45-related proteins may contribute to the degradation of myosin in conditions such as heart failure and muscle wasting.
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Landsverk et al. (2007) studied Myosin assembly and muscle function. UNC-45 overexpression and partial proteasome inhibition vs. Wild-type or loss-of-function mutations was evaluated on Myosin accumulation and worm motility. Overexpression of UNC-45 in C. elegans leads to decreased myosin content and mild paralysis via ubiquitin/proteasome degradation, which is restored by partial proteasome inhibition.
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