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Journal Article

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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Jung,  S.
Research Group of Synaptic Nanophysiology, MPI for Biophysical Chemistry, Max Planck Society;

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Moser,  T.
Research Group of Synaptic Nanophysiology, MPI for Biophysical Chemistry, Max Planck Society;

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2326463_Suppl_1.pdf
(Supplementary material), 810KB

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(Supplementary material), 4MB

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(Supplementary material), 4MB

2326463_Suppl_4.zip
(Supplementary material), 118KB

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(Supplementary material), 303KB

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(Supplementary material), 119KB

2326463_Suppl_7.zip
(Supplementary material), 564KB

Citation

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.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-14D3-2
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.