Neurobiology Curriculum, University of North Carolina, Chapel Hill, Chapel Hill, NC.
Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, Chapel Hill, NC.
J Cell Biol. 2020 Jan 6;219(1). doi: 10.1083/jcb.201902088.
Appropriate axon guidance is necessary to form accurate neuronal connections. Axon guidance cues that stimulate cytoskeletal reorganization within the growth cone direct axon navigation. Filopodia at the growth cone periphery have long been considered sensors for axon guidance cues, yet how they respond to extracellular cues remains ill defined. Our previous work found that the filopodial actin polymerase VASP and consequently filopodial stability are negatively regulated via nondegradative TRIM9-dependent ubiquitination. Appropriate VASP ubiquitination and deubiquitination are required for axon turning in response to the guidance cue netrin-1. Here we show that the TRIM9-related protein TRIM67 outcompetes TRIM9 for interacting with VASP and antagonizes TRIM9-dependent VASP ubiquitination. The surprising antagonistic roles of two closely related E3 ubiquitin ligases are required for netrin-1-dependent filopodial responses, axon turning and branching, and fiber tract formation. We suggest a novel model in which coordinated regulation of VASP ubiquitination by a pair of interfering ligases is a critical element of VASP dynamics, filopodial stability, and axon guidance.
适当的轴突导向对于形成准确的神经元连接是必要的。刺激生长锥内细胞骨架重排的轴突导向线索指导轴突导航。生长锥边缘的丝状伪足长期以来被认为是轴突导向线索的传感器，但它们如何对细胞外线索做出反应仍不清楚。我们之前的工作发现，丝状伪足肌动蛋白聚合酶 VASP 及其稳定性受到 TRIM9 依赖性非降解泛素化的负调控。适当的 VASP 泛素化和去泛素化对于响应导向线索 netrin-1 的轴突转向是必需的。在这里，我们表明，与 TRIM9 相关的蛋白 TRIM67 与 VASP 竞争相互作用，并拮抗 TRIM9 依赖性 VASP 泛素化。两种密切相关的 E3 泛素连接酶的惊人拮抗作用对于 netrin-1 依赖性丝状伪足反应、轴突转向和分支以及纤维束形成是必需的。我们提出了一个新的模型，其中由一对干扰连接酶协调调节 VASP 泛素化是 VASP 动力学、丝状伪足稳定性和轴突导向的关键因素。
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