Manickam Rohini, Rotty Jeremy D
bioRxiv. 2025 May 14:2025.05.13.653717. doi: 10.1101/2025.05.13.653717.
Dynamic cycles of actin remodeling drive membrane protrusion and retraction events essential for macrophage function. Phosphoregulation of actin-associated proteins plays a key role, but the factors that determine the spatiotemporal balance between kinases and phosphatases is less well understood in this context. Here, we identify the Protein Phosphatase 1 (PP1)-binding protein Phactr4 as a critical regulator of cytoskeletal remodeling. Phactr4 loss disrupts lamellipodial architecture, which results in uncoordinated migration and disrupted iC3b-mediated phagocytosis. Unstable membrane dynamics underlie the Phactr4 knockdown phenotypes. Phactr4 is recruited to the leading edge via interaction with active Arp2/3 complex, and strongly correlates with membrane retraction. Phactr4 loss leads to ezrin hyperphosphorylation, and membrane protrusion defects in these cells are reversed by ezrin inhibition. Our findings position Phactr4 as a critical PP1-dependent coordinator of cytoskeletal remodeling during macrophage migration and phagocytosis. Recent reports have linked Phactr4 to several human disease states, which may be due to its influence on actin dynamics.
肌动蛋白重塑的动态循环驱动着对巨噬细胞功能至关重要的膜突出和回缩事件。肌动蛋白相关蛋白的磷酸化调节起着关键作用，但在此背景下，决定激酶和磷酸酶之间时空平衡的因素尚不太清楚。在这里，我们确定蛋白磷酸酶1（PP1）结合蛋白Phactr4是细胞骨架重塑的关键调节因子。Phactr4的缺失破坏了片状伪足结构，导致迁移不协调和iC3b介导的吞噬作用受损。不稳定的膜动力学是Phactr4基因敲低表型的基础。Phactr4通过与活性Arp2/3复合体相互作用被招募到前沿，并与膜回缩密切相关。Phactr4的缺失导致埃兹蛋白过度磷酸化，这些细胞中的膜突出缺陷通过抑制埃兹蛋白得以逆转。我们的研究结果表明，Phactr4是巨噬细胞迁移和吞噬过程中细胞骨架重塑的关键PP1依赖性协调因子。最近的报道将Phactr4与几种人类疾病状态联系起来，这可能是由于它对肌动蛋白动力学的影响。
