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

Vogl, C., Panou, I., Yamanbaeva, G., Wichmann, C., Mangosing, S. J., Vilardi, F., et al. (2016). Tryptophan-rich basic protein (WRB) mediates insertion of the tail-anchored protein otoferlin and is required for hair cell exocytosis and hearing. The EMBO Journal, 35(23), 2536-2552. doi:10.15252/embj.201593565.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002B-14D3-2 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-28FF-D
Genre: Journal Article

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 Creators:
Vogl, C., Author
Panou, I., Author
Yamanbaeva, G., Author
Wichmann, C., Author
Mangosing, S. J., Author
Vilardi, F., Author
Indzhykulian, A. A., Author
Pangršič, T., Author
Santarelli, R., Author
Rodriguez-Ballesteros, M., Author
Weber, T., Author
Jung, S.1, Author              
Cardenas, E., Author
Wu, X., Author
Wojcik, S. M., Author
Kwan, K. Y., Author
Del Castillo, I., Author
Schwappach, B.2, Author              
Strenzke, N., Author
Corey, D. P., Author
Lin, S. Y., AuthorMoser, T.1, Author               more..
Affiliations:
1Research Group of Synaptic Nanophysiology, MPI for Biophysical Chemistry, Max Planck Society, ou_2205655              
2Max Planck Fellow Blanche Schwappach, ou_1548137              

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Free keywords: Deafness; Endoplasmic reticulum; Protein targeting; Synapse; Tail‐anchored protein
 Abstract: The transmembrane recognition complex (TRC40) pathway mediates the insertion of tail-anchored (TA) proteins into membranes. Here, we demonstrate that otoferlin, a TA protein essential for hair cell exocytosis, is inserted into the endoplasmic reticulum (ER) via the TRC40 pathway. We mutated the TRC40 receptor tryptophan-rich basic protein (Wrb) in hair cells of zebrafish and mice and studied the impact of defective TA 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 (IHCs) displayed normal numbers of afferent synapses, Ca2+ channels, and membrane-proximal vesicles, but contained fewer ribbon-associated vesicles. Patch-clamp of IHCs revealed impaired synaptic vesicle replenishment. In vivo recordings from postsynaptic spiral ganglion neurons showed a use-dependent reduction in sound-evoked spiking, corroborating the notion of impaired IHC vesicle replenishment. A human mutation affecting the transmembrane domain of otoferlin impaired its ER targeting and caused an auditory synaptopathy. We conclude that the TRC40 pathway is critical for hearing and propose that otoferlin is an essential substrate of this pathway in hair cells.

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Language(s): eng - English
 Dates: 2016-07-252016-12-01
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.15252/embj.201593565
 Degree: -

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Title: The EMBO Journal
Source Genre: Journal
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Pages: - Volume / Issue: 35 (23) Sequence Number: - Start / End Page: 2536 - 2552 Identifier: -