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Vogl, Christian; Panou, Iliana; Yamanbaeva, Gulnara; Wichmann, Carolin; Mangosing, Sara J; Vilardi, Fabio; Indzhykulian, Artur A; Pangršič, Tina; Santarelli, Rosamaria; Rodriguez‐Ballesteros, Montserrat; Weber, Thomas; Jung, Sangyong; Cardenas, Elena; Wu, Xudong; Wojcik, Sonja M; Kwan, Kelvin Y; del Castillo, Ignacio; Schwappach, Blanche; Strenzke, Nicola; Corey, David P; Lin, Shuh‐Yow; Moser, Tobias

Tryptophan‐rich basic protein (WRB) mediates insertion of the tail‐anchored protein otoferlin and is required for hair cell exocytosis and hearing

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  • Medientyp: E-Artikel
  • Titel: Tryptophan‐rich basic protein (WRB) mediates insertion of the tail‐anchored protein otoferlin and is required for hair cell exocytosis and hearing
  • Beteiligte: Vogl, Christian; Panou, Iliana; Yamanbaeva, Gulnara; Wichmann, Carolin; Mangosing, Sara J; Vilardi, Fabio; Indzhykulian, Artur A; Pangršič, Tina; Santarelli, Rosamaria; Rodriguez‐Ballesteros, Montserrat; Weber, Thomas; Jung, Sangyong; Cardenas, Elena; Wu, Xudong; Wojcik, Sonja M; Kwan, Kelvin Y; del Castillo, Ignacio; Schwappach, Blanche; Strenzke, Nicola; Corey, David P; Lin, Shuh‐Yow; Moser, Tobias
  • Erschienen: Springer Science and Business Media LLC, 2016
  • Erschienen in: The EMBO Journal
  • Sprache: Englisch
  • DOI: 10.15252/embj.201593565
  • ISSN: 0261-4189; 1460-2075
  • Schlagwörter: General Immunology and Microbiology ; General Biochemistry, Genetics and Molecular Biology ; Molecular Biology ; General Neuroscience
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>The transmembrane recognition complex (<jats:styled-content style="fixed-case">TRC</jats:styled-content>40) pathway mediates the insertion of tail‐anchored (<jats:styled-content style="fixed-case">TA</jats:styled-content>) proteins into membranes. Here, we demonstrate that otoferlin, a <jats:styled-content style="fixed-case">TA</jats:styled-content> protein essential for hair cell exocytosis, is inserted into the endoplasmic reticulum (<jats:styled-content style="fixed-case">ER</jats:styled-content>) via the <jats:styled-content style="fixed-case">TRC</jats:styled-content>40 pathway. We mutated the <jats:styled-content style="fixed-case">TRC</jats:styled-content>40 receptor tryptophan‐rich basic protein (Wrb) in hair cells of zebrafish and mice and studied the impact of defective <jats:styled-content style="fixed-case">TA</jats:styled-content> protein insertion. Wrb disruption reduced otoferlin levels in hair cells and impaired hearing, which could be restored in zebrafish by transgenic Wrb rescue and otoferlin overexpression. Wrb‐deficient mouse inner hair cells (<jats:styled-content style="fixed-case">IHC</jats:styled-content>s) displayed normal numbers of afferent synapses, Ca<jats:sup>2+</jats:sup> channels, and membrane‐proximal vesicles, but contained fewer ribbon‐associated vesicles. Patch‐clamp of <jats:styled-content style="fixed-case">IHC</jats:styled-content>s revealed impaired synaptic vesicle replenishment. <jats:italic>In vivo</jats:italic> recordings from postsynaptic spiral ganglion neurons showed a use‐dependent reduction in sound‐evoked spiking, corroborating the notion of impaired <jats:styled-content style="fixed-case">IHC</jats:styled-content> vesicle replenishment. A human mutation affecting the transmembrane domain of otoferlin impaired its <jats:styled-content style="fixed-case">ER</jats:styled-content> targeting and caused an auditory synaptopathy. We conclude that the <jats:styled-content style="fixed-case">TRC</jats:styled-content>40 pathway is critical for hearing and propose that otoferlin is an essential substrate of this pathway in hair cells.</jats:p>
  • Zugangsstatus: Freier Zugang