Biomedical Center Munich (BMC), Walter Brendel Center of Experimental Medicine, Institute of Cardiovascular Physiology and Pathophysiology, University Hospital, Ludwig Maximilians University Munich, Munich, Germany.
Institute of Science and Technology Austria, Klosterneuburg, Austria.
EMBO J. 2023 Dec 11;42(24):e114557. doi: 10.15252/embj.2023114557. Epub 2023 Nov 21.
Motile cells encounter microenvironments with locally heterogeneous mechanochemical composition. Individual compositional parameters, such as chemokines and extracellular matrix pore sizes, are well known to provide guidance cues for pathfinding. However, motile cells face diverse cues at the same time, raising the question of how they respond to multiple and potentially competing signals on their paths. Here, we reveal that amoeboid cells require nuclear repositioning, termed nucleokinesis, for adaptive pathfinding in heterogeneous mechanochemical micro-environments. Using mammalian immune cells and the amoeba Dictyostelium discoideum, we discover that frequent, rapid and long-distance nucleokinesis is a basic component of amoeboid pathfinding, enabling cells to reorientate quickly between locally competing cues. Amoeboid nucleokinesis comprises a two-step polarity switch and is driven by myosin-II forces that readjust the nuclear to the cellular path. Impaired nucleokinesis distorts path adaptions and causes cellular arrest in the microenvironment. Our findings establish that nucleokinesis is required for amoeboid cell navigation. Given that many immune cells, amoebae, and some cancer cells utilize an amoeboid migration strategy, these results suggest that nucleokinesis underlies cellular navigation during unicellular biology, immunity, and disease.
运动细胞会遇到局部机械化学组成异质的微环境。个别组成参数，如趋化因子和细胞外基质的孔径大小，众所周知可为寻径提供导向线索。然而，运动细胞同时面临着多种线索，这就提出了一个问题，即它们如何对路径上的多种潜在竞争信号做出反应。在这里，我们揭示了变形虫细胞需要核重定位，即核迁移，以适应机械化学异质微环境中的寻径。通过使用哺乳动物免疫细胞和变形虫盘基网柄菌，我们发现频繁、快速和远距离的核迁移是变形虫寻径的基本组成部分，使细胞能够在局部竞争线索之间快速重新定向。变形虫的核迁移包括两步极性转换，由肌球蛋白 II 力驱动，将核重新调整到细胞路径上。核迁移受损会扭曲路径适应性，并导致细胞在微环境中停滞。我们的发现确立了核迁移是变形虫细胞导航所必需的。鉴于许多免疫细胞、变形虫和一些癌细胞采用变形虫迁移策略，这些结果表明，核迁移是单细胞生物学、免疫和疾病过程中细胞导航的基础。
