期刊
EMBO JOURNAL
卷 35, 期 23, 页码 2536-2552出版社
WILEY
DOI: 10.15252/embj.201593565
关键词
deafness; endoplasmic reticulum; protein targeting; synapse; tail-anchored protein
资金
- German Research Foundation through the Collaborative Research Center [889]
- Center for Molecular Physiology of the Brain [FZT-103]
- Leibniz Program
- Deafness Research Foundation
- UCSD Foundation
- National Institutes of Health (NIH) [R01-DC000304, R01-DC002281]
- Instituto de Salud Carlos III, Madrid, Spain [FIS PI14/01162]
- European Regional Development Fund
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据