Stereociliary localization and function of the tip-link protein PCDH15-CD2 are regulated by the PDZ-scaffold NHERF-1
- 1University of Virginia Health System
Abstract
Sensory hair cells in the inner ear convert mechanical sound deflections into electrical signals via the stereociliary hair bundle on their apical surface. Proper bundle function requires that structural, adhesion, and motor proteins be delivered to specific stereocilia sub-compartments and maintained at precise levels throughout life, yet the underlying mechanisms remain poorly understood. Here we investigated how spatiotemporal localization of Protocadherin-15 (PCDH15), a component of kinociliary links, transient lateral links, and tip links, is regulated in mouse auditory hair cells. Using biochemical assays in vitro, we identified the PDZ-domain scaffolds NHERF-1/2 as direct binding partners of CD2, a PCDH15 isoform essential for hearing. We mapped the interaction to NHERF-1's PDZ1 domain and CD2's PDZ-binding motif (PBM), and showed that this binding is regulated by phosphorylation of the CD2 PBM. Using Nherf1 knockout and Pcdh15-CD2 knock-in mice defective in this interaction, we found CD2-NHERF-1 binding is required for proper CD2 levels and localization in the developing hair bundle. Loss of this interaction largely spared early bundle morphogenesis and MET function but caused high-frequency hearing loss and degeneration of the shortest stereociliary row in adult mice. Together, these findings define an important regulatory mechanism with therapeutic relevance for hair bundle repair.
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BibTeX
@misc{adylkhan2026stereociliary,
title = {{Stereociliary localization and function of the tip-link protein PCDH15-CD2 are regulated by the PDZ-scaffold NHERF-1}},
author = {A. Adylkhan and A. Andreeva and X. Qiu and Z. Shatkenova and P. Wilson and A. Lim and D. Son and R. Huang and U. Mueller and X. Lu},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.762349},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762349v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Stereociliary localization and function of the tip-link protein PCDH15-CD2 are regulated by the PDZ-scaffold NHERF-1
AU - A. Adylkhan
AU - A. Andreeva
AU - X. Qiu
AU - Z. Shatkenova
AU - P. Wilson
AU - A. Lim
AU - D. Son
AU - R. Huang
AU - U. Mueller
AU - X. Lu
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.762349
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.762349v1
AB - Sensory hair cells in the inner ear convert mechanical sound deflections into electrical signals via the stereociliary hair bundle on their apical surface. Proper bundle function requires that structural, adhesion, and motor proteins be delivered to specific stereocilia sub-compartments and maintained at precise levels throughout life, yet the underlying mechanisms remain poorly understood. Here we investigated how spatiotemporal localization of Protocadherin-15 (PCDH15), a component of kinociliary links, transient lateral links, and tip links, is regulated in mouse auditory hair cells. Using biochemical assays in vitro, we identified the PDZ-domain scaffolds NHERF-1/2 as direct binding partners of CD2, a PCDH15 isoform essential for hearing. We mapped the interaction to NHERF-1's PDZ1 domain and CD2's PDZ-binding motif (PBM), and showed that this binding is regulated by phosphorylation of the CD2 PBM. Using Nherf1 knockout and Pcdh15-CD2 knock-in mice defective in this interaction, we found CD2-NHERF-1 binding is required for proper CD2 levels and localization in the developing hair bundle. Loss of this interaction largely spared early bundle morphogenesis and MET function but caused high-frequency hearing loss and degeneration of the shortest stereociliary row in adult mice. Together, these findings define an important regulatory mechanism with therapeutic relevance for hair bundle repair.
ER -