Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, viale GB Morgagni 50, 50134 Florence, Italy.
Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla 3, 50134, Florence, Italy.
Biochim Biophys Acta Mol Cell Res. 2019 Apr;1866(4):554-565. doi: 10.1016/j.bbamcr.2018.12.007. Epub 2019 Jan 3.
Hearing loss is among the most prevalent sensory impairments in humans. Cochlear implantable devices represent the current therapies for hearing loss but have various shortcomings. ERM (ezrin- radixin -moesin) are a family of adaptor proteins that link plasma membrane with actin cytoskeleton, playing a crucial role in cell morphology and in the formation of membrane protrusions. Recently, bioactive sphingolipids have emerged as regulators of ERM proteins. Sphingosine 1-phosphate (S1P) is a pleiotropic sphingolipid which regulates fundamental cellular functions such as proliferation, survival, migration as well as processes such as development and inflammation mainly via ligation to its specific receptors S1PR (S1P). Experimental findings demonstrate a key role for S1P signaling axis in the maintenance of auditory function. Preservation of cellular junctions is a fundamental function both for S1P and ERM proteins, crucial for the maintenance of cochlear integrity. In the present work, S1P was found to activate ERM in a S1P-dependent manner in murine auditory epithelial progenitors US/VOT-E36. S1P-induced ERM activation potently contributed to actin cytoskeletal remodeling and to the appearance of ionic currents and membrane passive properties changes typical of more differentiated cells. Moreover, PKC and Akt activation was found to mediate S1P-induced ERM phosphorylation. The obtained findings contribute to demonstrate the role of S1P signaling pathway in inner ear biology and to disclose potential innovative therapeutical approaches in the field of hearing loss prevention and treatment.
听力损失是人类最常见的感觉障碍之一。耳蜗植入设备是目前治疗听力损失的方法，但存在各种缺点。ERM（ezrin-radixin-moesin）是一组衔接蛋白，将质膜与肌动蛋白细胞骨架连接起来，在细胞形态和膜突起的形成中起着至关重要的作用。最近，生物活性鞘脂已成为 ERM 蛋白的调节剂。1-磷酸鞘氨醇（S1P）是一种多效性鞘脂，通过与其特定受体 S1PR（S1P）结合，主要调节增殖、存活、迁移等基本细胞功能以及发育和炎症等过程。实验结果表明，S1P 信号轴在维持听觉功能中起着关键作用。细胞连接的保持是 S1P 和 ERM 蛋白的基本功能，对耳蜗完整性的维持至关重要。在本工作中，发现 S1P 以 S1P 依赖的方式激活小鼠听觉上皮祖细胞 US/VOT-E36 中的 ERM。S1P 诱导的 ERM 激活有力地促进了肌动蛋白细胞骨架的重塑，并出现了典型的更分化细胞的离子电流和膜被动特性变化。此外，还发现 PKC 和 Akt 的激活介导了 S1P 诱导的 ERM 磷酸化。这些发现有助于证明 S1P 信号通路在内耳生物学中的作用，并揭示听力损失预防和治疗领域的潜在创新治疗方法。
