GIGA-Neurosciences, Unit of Cell and Tissue Biology, University of Liège, C.H.U B36, B-4000 Liège, Belgium.
GIGA-Neurosciences, Unit of Cell and Tissue Biology, University of Liège, C.H.U B36, B-4000 Liège, Belgium.
Hear Res. 2021 Feb;400:108137. doi: 10.1016/j.heares.2020.108137. Epub 2020 Nov 30.
In the cochlea, connexins 26 (Cx26) and 30 (Cx30) largely co-assemble into heteromeric gap junctions, which connect adjacent non-sensory epithelial cells. These channels are believed to ensure the rapid removal of K away from the base of sensory hair cells, resulting in K recycling back to the endolymph to maintain cochlear homeostasis. Many of the mutations in GJB2 and GJB6, which encode CX26 and CX30, impair the formation of membrane channels and cause autosomal hearing loss in humans. Although recent advances have been made, several important questions remain about connexin trafficking and gap junction biogenesis. Here we show that tricellular adherens junctions present at the crossroad between adjacent gap junction plaques, provide an unexpected cell surface delivery platform for Cx26/Cx30 oligomers. Using an in situ proximity ligation assay, we detected the presence of non-junctional Cx26/Cx30 oligomers within lipid raft-enriched tricellular junction sites. In addition, we observed that cadherin homophilic interactions are critically involved in microtubule-mediated trafficking of Cx26/Cx30 oligomers to the cell surface. Overall, our results unveil an unexpected role for tricellular junctions in the trafficking and assembly of membrane channels.
在耳蜗中，连接蛋白 26（Cx26）和 30（Cx30）主要组装成异源间隙连接，将相邻的非感觉上皮细胞连接起来。这些通道被认为可以确保 K 迅速从感觉毛细胞的基部移除，从而使 K 循环回内淋巴以维持耳蜗内环境稳定。编码 CX26 和 CX30 的 GJB2 和 GJB6 的许多突变会损害膜通道的形成，并导致人类常染色体听力损失。尽管最近取得了一些进展，但关于连接蛋白运输和间隙连接生物发生仍有几个重要问题尚未解决。在这里，我们表明，相邻间隙连接斑块交叉处的三细胞黏附连接提供了一个意想不到的细胞表面递呈平台，用于 Cx26/Cx30 寡聚体。通过原位邻近连接分析，我们在富含脂质筏的三细胞连接部位检测到非连接性 Cx26/Cx30 寡聚体的存在。此外，我们观察到钙黏蛋白同源相互作用对于 Cx26/Cx30 寡聚体通过微管向细胞表面的运输至关重要。总的来说，我们的结果揭示了三细胞连接在膜通道运输和组装中的一个意想不到的作用。
