Abstract
Myosins play essential roles in the development and function of auditory organs and multiple myosin genes are associated with hereditary forms of deafness. Using a forward genetic screen in Drosophila, we identified an E3 ligase, Ubr3, as an essential gene for auditory organ development. Ubr3 negatively regulates the mono-ubiquitination of non-muscle Myosin II, a protein associated with hearing loss in humans. The mono-ubiquitination of Myosin II promotes its physical interaction with Myosin VIIa, a protein responsible for Usher syndrome type IB. We show that ubr3 mutants phenocopy pathogenic variants of Myosin II and that Ubr3 interacts genetically and physically with three Usher syndrome proteins. The interactions between Myosin VIIa and Myosin IIa are conserved in the mammalian cochlea and in human retinal pigment epithelium cells. Our work reveals a novel mechanism that regulates protein complexes affected in two forms of syndromic deafness and suggests a molecular function for Myosin IIa in auditory organs.
Highlights
Mechanosensory receptor cells have organelles derived from modified cilia or microvilli that contain protein complexes dedicated to the detection of, and adaptation to, mechanical force
We show that ubr3 mutations are phenotypically similar to known pathogenic variants of Myosin II and that Ubr3 physically and genetically interacts with Drosophila homologues of the Usher syndrome proteins Protocadherin 15 (Pcdh15) and Sans
Using a forward genetic screen based on the phenotype associated with the loss of MyoVIIa (Todi et al, 2005a, 2008), we identified a set of proteins that affect ubiquitination and regulate the function of MyoVIIa
Summary
Mechanosensory receptor cells have organelles derived from modified cilia or microvilli that contain protein complexes dedicated to the detection of, and adaptation to, mechanical force. A family of eukaryotic actin-dependent motor proteins, play key roles in the assembly and function of mechanosensory protein complexes. Pathogenic variants of six different myosin genes cause syndromic and non-syndromic deafness, and in many cases these myosins regulate either the assembly of the mechanotransduction apparatus of sensory hair cells, or constitute an integral part of the mechanotransduction complex itself (Petit and Richardson, 2009). Myosin VIIa is a motor protein present in the tips of hair cell stereocilia where mechanotransduction occurs but it is present in the cuticular plate that is important for the growth and stability of the stereociliary hair bundle (Ahmed et al, 2013). Pathogenic variants of MYO7A, the human homologue of myosin VIIa, can cause Usher syndrome, the leading cause of deaf-blindness
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