title: The E3 ligase Ubr3 regulates Usher syndrome and MYH9 disorder proteins in the auditory organs of Drosophila and mammals.
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.
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.
authors.forename: Tongchao
authors.initials: T
authors.lastname: Li
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Department of Neurology, Baylor College of Medicine, Houston, United States.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Giagtzoglou
authors.affiliation: Department of Biology, University of Iowa, Iowa City, United States.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Eberl
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.
authors.forename: Sonal Nagarkar
authors.initials: SN
authors.lastname: Jaiswal
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, United States.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Cai
authors.affiliation: Department of Cell and Systems Biology, University of Toronto, Toronto, Canada.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Godt
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Department of Neuroscience, Baylor College of Medicine, Houston, United States.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Groves
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, United States.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, United States.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States.|Department of Neuroscience, Baylor College of Medicine, Houston, United States.
authors.forename: Hugo J
authors.identifier: 0000-0001-5992-5989
authors.initials: HJ
authors.lastname: Bellen
mesh_terms: D000818:Animals; D002460:Cell Line; D003051:Cochlea / Q000196:embryology*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005820:Genetic Testing; D006801:Humans; D000081412:Myosin VIIa; D009218:Myosins / Q000378:metabolism*; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; C000631455:MYO7A protein, human; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; C000631458:myosin 7a, Drosophila; D044767:Ubiquitin-Protein Ligases; D024507:Nonmuscle Myosin Type IIA; D009218:Myosins; C000599363:Ubr3 protein, Drosophila
keywords: D. melanogaster; MYH9 disorder; Myosin; Usher syndrome; cell biology; developmental biology; hearing; human; mouse; stem cells; ubiquitination