Translational readthrough generates new astrocyte AQP4 isoforms that modulate supramolecular clustering, glial endfeet localization, and water transport
Translational readthrough generates new astrocyte AQP4 isoforms that modulate supramolecular clustering, glial endfeet localization, and water transport
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DOI：
10.1002/glia.23126
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发表时间：
2017-05-01
期刊：
影响因子：
6.2
通讯作者：
Frigeri, Antonio
中科院分区：
文献类型：
--
作者：
De Bellis, Manuela;Pisani, Francesco;Frigeri, Antonio
水稳态的调节是中枢神经系统病理生理学的中心特征。在这种情况下，一些证据表明，水通道水通道蛋白-4（AQP 4）及其质膜超分子组织作为关键要素发挥着至关重要的作用。在这里，我们证明了AQP 4的其他亚型的组织中的表达，其特征在于通过编程翻译通读产生的C-末端延伸。这些扩展的亚型（AQP 4 ex）显示血管周围极化和肌营养不良蛋白依赖池中的表达。AQP 4 ex降低了超分子聚集趋势，并允许AQP 4与促突触蛋白相互作用。此外，在AQP 4 ex的扩展C-末端的两个丝氨酸的定点突变显示出潜在的调节水渗透性的磷酸化。最后，AQP 4 ex的表达可以被庆大霉素处理正向调节，证明了调节AQP 4翻译通读频率的可能性。这种新的调节机制可能具有重要的病理生理学意义的条件下，已报告的改变AQP 4结构。
Regulation of water homeostasis is a central feature of central nervous system pathophysiology. In this context, several lines of evidence suggest a crucial role for the water channel aquaporin-4 (AQP4) and its plasma membrane supramolecular organization as the key element. Here, we demonstrate the expression in tissues of additional isoforms of AQP4 characterized by a C-terminal extension generated by programmed translational readthrough. These extended isoforms (AQP4ex) display a perivascular polarization and expression in dystrophin-dependent pools. AQP4ex reduces supramolecular clustering tendency and allows AQP4 interactions with syntrophin. Furthermore, site-directed mutagenesis of two serines in the extended C-terminus of AQP4ex showed potential regulation of water permeability by phosphorylation. Finally, AQP4ex expression can be positively modulated by gentamicin treatment, demonstrating the possibility of regulating the AQP4 translational readthrough frequency. This novel regulatory mechanism could have important pathophysiological implications for conditions in which alternations have been reported in AQP4 structure.