title: Complexes of Usher proteins preassemble at the endoplasmic reticulum and are required for trafficking and ER homeostasis.
abstract: Usher syndrome (USH), the leading cause of hereditary combined hearing and vision loss, is characterized by sensorineural deafness and progressive retinal degeneration. Mutations in several different genes produce USH, but the proximal cause of sensory cell death remains mysterious. We adapted a proximity ligation assay to analyze associations among three of the USH proteins, Cdh23, Harmonin and Myo7aa, and the microtubule-based transporter Ift88 in zebrafish inner ear mechanosensory hair cells. We found that the proteins are in close enough proximity to form complexes and that these complexes preassemble at the endoplasmic reticulum (ER). Defects in any one of the three USH proteins disrupt formation and trafficking of the complex and result in diminished levels of the other proteins, generalized trafficking defects and ER stress that triggers apoptosis. ER stress, thus, contributes to sensory hair cell loss and provides a new target to explore for protective therapies for USH.
authors.affiliation: Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Blanco-Sánchez
authors.forename: Aurélie
authors.initials: A
authors.lastname: Clément
authors.forename: Javier
authors.initials: J
authors.lastname: Fierro
authors.forename: Philip
authors.initials: P
authors.lastname: Washbourne
authors.forename: Monte
authors.initials: M
authors.lastname: Westerfield
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D006199:Hair Cells, Auditory, Inner; D006706:Homeostasis; D008465:Mechanoreceptors / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport; D013347:Subcellular Fractions / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes; D029961:Zebrafish Proteins
keywords: Cadherin23; ER stress; Hair cell; Harmonin; Ift88; Myo7aa; Trafficking; Usher syndrome; Zebrafish