INSERM, UMR1048, Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, 31432 Toulouse, France.
INSERM, UMR1043, Plateau Technique D'imagerie Cellulaire, Centre de Physiopathologie de Toulouse Purpan, 31024 Toulouse, France.
Nat Commun. 2014 Jun 6;5:4080. doi: 10.1038/ncomms5080.
PtdIns5P is a lipid messenger acting as a stress-response mediator in the nucleus, and known to maintain cell activation through traffic alterations upon bacterial infection. Here, we show that PtdIns5P regulates actin dynamics and invasion via recruitment and activation of the exchange factor Tiam1 and Rac1. Restricted Rac1 activation results from the binding of Tiam1 DH-PH domains to PtdIns5P. Using an assay that mimics Rac1 membrane anchoring by using Rac1-His and liposomes containing Ni(2+)-NTA modified lipids, we demonstrate that intrinsic Tiam1 DH-PH activity increases when Rac1 is anchored in a PtdIns5P-enriched environment. This pathway appears to be general since it is valid in different pathophysiological models: receptor tyrosine kinase activation, bacterial phosphatase IpgD expression and the invasive NPM-ALK(+) lymphomas. The discovery that PtdIns5P could be a keystone of GTPases and cytoskeleton spatiotemporal regulation opens important research avenues towards unravelling new strategies counteracting cell invasion.
PtdIns5P 是一种脂质信使，作为细胞核中的应激反应介质，已知在细菌感染时通过改变运输来维持细胞激活。在这里，我们表明 PtdIns5P 通过募集和激活交换因子 Tiam1 和 Rac1 来调节肌动蛋白动力学和入侵。受限制的 Rac1 激活是由于 Tiam1 DH-PH 结构域与 PtdIns5P 的结合。使用一种模拟 Rac1 通过 Rac1-His 和含有 Ni(2+)-NTA 修饰脂质的脂质体锚定在膜上的测定法，我们证明了当 Rac1 锚定在富含 PtdIns5P 的环境中时，Tiam1 DH-PH 活性会增加。由于该途径在不同的病理生理模型中是有效的，因此它似乎是普遍存在的：受体酪氨酸激酶激活、细菌磷酸酶 IpgD 表达和侵袭性 NPM-ALK(+)淋巴瘤。发现 PtdIns5P 可以成为 GTPases 和细胞骨架时空调节的关键因素，为揭示新的策略以对抗细胞侵袭开辟了重要的研究途径。
