Author response: The E3 ligase Ubr3 regulates Usher syndrome and MYH9 disorder proteins in the auditory organs of Drosophila and mammals

Over half of the world’s population has hearing loss by the age of 65, and inherited forms of deafness are responsible for many of the hearing impairments in newborn children. Because the auditory organs that enable insects and mammals to hear work in similar ways, we have learnt a lot about genetic forms of deafness from identifying faulty genes in humans and mice, and studying their effects in model organisms. Sensory cells in the inner ear respond to sound by detecting vibrations in the air and converting them into electrical impulses. A family of motor proteins called myosins play key roles in this conversion process. Mutations in the gene that produces one of these proteins, called myosin VIIa, cause an inherited deaf-blind disorder called Usher syndrome. Mutations in the gene for another type of myosin protein, called myosin II, also cause disorders associated with hearing loss, but it is not clear how they produce such effects. Li et al. have used Drosophila fruit flies to explore the role of myosin proteins in hearing by looking for genes that prevent the insect's auditory organ from developing or working properly. The search identified one gene called E3 ubiquitin ligase (ubr3), which is required for the auditory organ to develop normally and had not previously been implicated in deafness. Mutating the ubr3 gene caused a defect similar to that seen for mutations in the gene that produces the fruit fly equivalent of myosin VIIa. Through genetic and biochemical studies, Li et al. found that in the fruit flies, myosin VIIa interacts with myosin II. This interaction is regulated by a chemical modification of myosin II that is controlled by ubr3. Li et al. showed that the equivalent mammalian proteins display the same behaviour in the cells of mammals. Therefore, mutations that affect myosin II alter how the protein interacts with myosin VIIa, which explains why myosin II is associated with deafness in humans. In addition, Li et al. found that three other proteins that have been shown to cause Usher syndrome in humans have equivalents in flies and play a role in fly hearing. This will allow the Drosophila auditory organ to be further developed as a model system for future studies of deafness genes, and should provide insights into how specific genes are required for proper hearing in mammals.

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