The E3 ligase Ubr3 regulates Usher syndrome and MYH9 disorder proteins in the auditory organs of Drosophila and mammals
Tongchao Li,
Nikolaos Giagtzoglou,
Daniel F Eberl,
Sonal Nagarkar Jaiswal,
Tiantian Cai,
Dorothea Godt,
Andrew K Groves,
Hugo J Bellen
Affiliations
Tongchao Li
Program in Developmental Biology, Baylor College of Medicine, Houston, United States
Nikolaos Giagtzoglou
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
Daniel F Eberl
Department of Biology, University of Iowa, Iowa City, United States
Sonal Nagarkar Jaiswal
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, United States
Tiantian Cai
Department of Neuroscience, Baylor College of Medicine, Houston, United States
Dorothea Godt
Department of Cell and Systems Biology, University of Toronto, Toronto, Canada
Andrew K Groves
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
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
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.
