School of Cellular and Molecular Medicine, Faculty of Biomedical Sciences, University of Bristol, Bristol BS8 1TD, UK.
Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
J Cell Sci. 2019 Feb 18;132(5):jcs224618. doi: 10.1242/jcs.224618.
The actin cytoskeleton is the engine that powers the inflammatory chemotaxis of immune cells to sites of tissue damage or infection. Here, we combine genetics with live imaging to investigate how cytoskeletal rearrangements drive macrophage recruitment to wounds in We find that the actin-regulatory protein Ena is a master regulator of lamellipodial dynamics in migrating macrophages, where it remodels the cytoskeleton to form linear filaments that can then be bundled together by the cross-linker Fascin (also known as Singed in flies). In contrast, the formin Dia generates rare, probing filopods for specialised functions that are not required for migration. The role of Ena in lamellipodial bundling is so fundamental that its overexpression increases bundling even in the absence of Fascin by marshalling the remaining cross-linking proteins to compensate. This reorganisation of the lamellipod generates cytoskeletal struts that push against the membrane to drive leading edge advancement and boost cell speed. Thus, Ena-mediated remodelling extracts the most from the cytoskeleton to power robust macrophage chemotaxis during their inflammatory recruitment to wounds.
细胞骨架是为免疫细胞向组织损伤或感染部位炎症趋化提供动力的引擎。在这里，我们将遗传学与实时成像相结合，研究细胞骨架重排如何驱动巨噬细胞向伤口募集。我们发现，肌动蛋白调节蛋白 Ena 是迁移巨噬细胞中片状伪足动力学的主要调节因子，它重塑细胞骨架以形成线性纤维，然后由交联蛋白 Fascin（在果蝇中也称为 Singed）将其捆绑在一起。相比之下，formin Dia 产生罕见的、探测状的丝状伪足，用于特殊功能，而这些功能对于迁移不是必需的。Ena 在片状伪足捆绑中的作用非常重要，以至于即使没有 Fascin，其过表达也会通过召集剩余的交联蛋白来代偿性地增加捆绑。这种片状伪足的重排产生了细胞骨架支柱，这些支柱可以推动细胞膜前进，从而提高前缘的推进速度，并提高细胞速度。因此，Ena 介导的重塑从细胞骨架中提取最多的物质，以在炎症期间巨噬细胞向伤口募集时提供强大的趋化作用。
