Eich Christina, Manzo Carlo, de Keijzer Sandra, Bakker Gert-Jan, Reinieren-Beeren Inge, García-Parajo Maria F, Cambi Alessandra
Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Postbox 9101, 6500 HB Nijmegen, The Netherlands.
ICFO-Institut de Ciencies Fotoniques, Mediterranean Technology Park, 08860 Castelldefels (Barcelona), Spain.
Sci Rep. 2016 Feb 12;6:20693. doi: 10.1038/srep20693.
Sphingolipids are essential constituents of the plasma membrane (PM) and play an important role in signal transduction by modulating clustering and dynamics of membrane receptors. Changes in lipid composition are therefore likely to influence receptor organisation and function, but how this precisely occurs is difficult to address given the intricacy of the PM lipid-network. Here, we combined biochemical assays and single molecule dynamic approaches to demonstrate that the local lipid environment regulates adhesion of integrin receptors by impacting on their lateral mobility. Induction of sphingomyelinase (SMase) activity reduced sphingomyelin (SM) levels by conversion to ceramide (Cer), resulting in impaired integrin adhesion and reduced integrin mobility. Dual-colour imaging of cortical actin in combination with single molecule tracking of integrins showed that this reduced mobility results from increased coupling to the actin cytoskeleton brought about by Cer formation. As such, our data emphasizes a critical role for the PM local lipid composition in regulating the lateral mobility of integrins and their ability to dynamically increase receptor density for efficient ligand binding in the process of cell adhesion.
鞘脂是质膜（PM）的重要组成部分，通过调节膜受体的聚集和动态变化在信号转导中发挥重要作用。因此，脂质组成的变化可能会影响受体的组织和功能，但鉴于质膜脂质网络的复杂性，很难确切说明这一过程是如何发生的。在这里，我们结合生化分析和单分子动力学方法，证明局部脂质环境通过影响整合素受体的侧向流动性来调节其黏附。鞘磷脂酶（SMase）活性的诱导通过转化为神经酰胺（Cer）降低了鞘磷脂（SM）水平，导致整合素黏附受损和整合素流动性降低。皮层肌动蛋白的双色成像与整合素的单分子追踪相结合表明，这种流动性降低是由于Cer形成导致与肌动蛋白细胞骨架的耦合增加所致。因此，我们的数据强调了质膜局部脂质组成在调节整合素侧向流动性及其在细胞黏附过程中动态增加受体密度以实现有效配体结合能力方面的关键作用。
