PUBLICATION
Tryptophan-rich basic protein (WRB) mediates insertion of the tail-anchored protein otoferlin and is required for hair cell exocytosis and hearing
- Authors
- Vogl, C., Panou, I., Yamanbaeva, G., Wichmann, C., Mangosing, S.J., Vilardi, F., Indzhykulian, A.A., Pangršič, T., Santarelli, R., Rodriguez-Ballesteros, M., Weber, T., Jung, S., Cardenas, E., Wu, X., Wojcik, S.M., Kwan, K.Y., Del Castillo, I., Schwappach, B., Strenzke, N., Corey, D.P., Lin, S.Y., Moser, T.
- ID
- ZDB-PUB-160728-13
- Date
- 2016
- Source
- The EMBO journal 35(23): 2536-2552 (Journal)
- Registered Authors
- Lin, Shuh-Yow, Weber, Thomas
- Keywords
- deafness, endoplasmic reticulum, protein targeting, synapse, tail‐anchored protein
- MeSH Terms
-
- Animals
- Arsenite Transporting ATPases/metabolism*
- Exocytosis*
- Gene Knockout Techniques
- Genetic Complementation Test
- Hair Cells, Auditory/metabolism*
- Hearing*
- Humans
- Membrane Proteins/metabolism*
- Mice
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism*
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 27458190 Full text @ EMBO J.
Citation
Vogl, C., Panou, I., Yamanbaeva, G., Wichmann, C., Mangosing, S.J., Vilardi, F., Indzhykulian, A.A., Pangršič, T., Santarelli, R., Rodriguez-Ballesteros, M., Weber, T., Jung, S., Cardenas, E., Wu, X., Wojcik, S.M., Kwan, K.Y., Del Castillo, I., Schwappach, B., Strenzke, N., Corey, D.P., Lin, S.Y., Moser, T. (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.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping