Distinct impacts of human co-chaperone UNC45 paralogs on <i>Drosophila</i> muscle development and function

Uncoordinated-45 (UNC45) is a conserved protein required for myosin accumulation during muscle development. Invertebrates have one unc-45 gene whereas vertebrates have two paralogs, UNC45A and UNC45B, which exhibit different expression patterns. We used the Drosophila model to investigate the ability of the vertebrate proteins to function in an invertebrate system, as well as the potential evolutionary redundancy of its human paralogs. Transgenic expression of either human UNC45 paralog early in indirect flight muscle development resulted in impaired flight, disordered muscle organization and unique sub-sarcomere localizations. We then generated chimeric proteins that replaced each of three Drosophila Unc-45 domains with their human cognates. We found that a chimera containing the myosin-binding UCS domain of human UNC45A impaired muscle function, whereas none of the UNC45B domain chimeras significantly impacted flight ability. Overall, our study shows that there is significant evolutionary divergence between vertebrate and invertebrate paralogs and that the human proteins differentially disrupt Drosophila myofibril assembly and function, suggesting that they are functionally unique.