Key Points Kindlin-3–PXN/LPXN interact by the F0 domain of Kindlin-3 and the LIM4 domain of PXN/LPXN. The Kindlin-3–PXN/LPXN link limits membrane blebbing and macrophage migration. Kindlin-3–PXN/LPXN interactions inhibit macrophage phagocytosis. Major myeloid cell functions from adhesion to migration and phagocytosis are mediated by integrin adhesion complexes, also known as adhesome. The presence of a direct integrin binding partner Kindlin-3 is crucial for these functions, and its lack causes severe immunodeficiency in humans. However, how Kindlin-3 is incorporated into the adhesome and how its function is regulated is poorly understood. In this study, using nuclear magnetic resonance spectroscopy, we show that Kindlin-3 directly interacts with paxillin (PXN) and leupaxin (LPXN) via G43/L47 within its F0 domain. Surprisingly, disruption of Kindlin-3–PXN/LPXN interactions in Raw 264.7 macrophages promoted cell spreading and polarization, resulting in upregulation of both general cell motility and directed cell migration, which is in a drastic contrast to the consequences of Kindlin-3 knockout. Moreover, disruption of Kindlin-3–PXN/LPXN binding promoted the transition from mesenchymal to amoeboid mode of movement as well as augmented phagocytosis. Thus, these novel links between Kindlin-3 and key adhesome members PXN/LPXN limit myeloid cell motility and phagocytosis, thereby providing an important immune regulatory mechanism.

中文翻译：

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Kindlin-3 与细胞骨架的连接控制巨噬细胞迁移和吞噬作用

关键点 Kindlin-3–PXN/LPXN 通过 Kindlin-3 的 F0 域和 PXN/LPXN 的 LIM4 域相互作用。Kindlin-3–PXN/LPXN 链接限制膜起泡和巨噬细胞迁移。Kindlin-3-PXN/LPXN 相互作用抑制巨噬细胞吞噬作用。从粘附到迁移和吞噬作用的主要骨髓细胞功能由整合素粘附复合物介导，也称为粘附体。整合素直接结合伴侣 Kindlin-3 的存在对这些功能至关重要，缺乏它会导致人类严重的免疫缺陷。然而，人们对 Kindlin-3 如何融入黏附体以及如何调节其功能知之甚少。在这项研究中，我们使用核磁共振波谱显示 Kindlin-3 通过其 F0 域内的 G43/L47 直接与桩蛋白 (PXN) 和亮白蛋白 (LPXN) 相互作用。出奇，Raw 264.7 巨噬细胞中 Kindlin-3-PXN/LPXN 相互作用的破坏促进了细胞扩散和极化，导致一般细胞运动和定向细胞迁移的上调，这与 Kindlin-3 敲除的后果形成鲜明对比。此外，Kindlin-3-PXN/LPXN 结合的破坏促进了从间充质到变形虫运动模式的转变以及增强的吞噬作用。因此，Kindlin-3 和关键粘附体成员 PXN/LPXN 之间的这些新联系限制了髓细胞的运动和吞噬作用，从而提供了一种重要的免疫调节机制。这与 Kindlin-3 淘汰赛的后果形成了鲜明的对比。此外，Kindlin-3-PXN/LPXN 结合的破坏促进了从间充质到变形虫运动模式的转变以及增强的吞噬作用。因此，Kindlin-3 和关键粘附体成员 PXN/LPXN 之间的这些新联系限制了髓细胞的运动和吞噬作用，从而提供了一种重要的免疫调节机制。这与 Kindlin-3 淘汰赛的后果形成了鲜明的对比。此外，Kindlin-3-PXN/LPXN 结合的破坏促进了从间充质到变形虫运动模式的转变以及增强的吞噬作用。因此，Kindlin-3 和关键粘附体成员 PXN/LPXN 之间的这些新联系限制了髓细胞的运动和吞噬作用，从而提供了一种重要的免疫调节机制。