FONDAP Geroscience Center for Brain Health and Metabolism, Santiago, Chile.
FONDAP Geroscience Center for Brain Health and Metabolism, Santiago, Chile; Department of Biology, Faculty of Sciences, Universidad de Chile, 7800024, Chile; The Buck Institute for Research on Aging, Novato, USA.
Free Radic Biol Med. 2018 Feb 20;116:101-113. doi: 10.1016/j.freeradbiomed.2018.01.008. Epub 2018 Jan 10.
The small RhoGTPase Rac1 is implicated in a variety of events related to actin cytoskeleton rearrangement. Remarkably, another event that is completely different from those related to actin regulation has the same relevance; the Rac1-mediated production of reactive oxygen species (ROS) through NADPH oxidases (NOX). Each outcome involves different Rac1 downstream effectors; on one hand, events related to the actin cytoskeleton require Rac1 to bind to WAVEs proteins and PAKs that ultimately promote actin branching and turnover, on the other, NOX-derived ROS production demands active Rac1 to be bound to a cytosolic activator of NOX. How Rac1-mediated signaling ends up promoting actin-related events, NOX-derived ROS, or both is poorly understood. Rac1 regulators, including scaffold proteins, are known to exert tight control over its functions. Hence, evidence of Rac1 regulatory events leading to both actin remodeling and NOX-mediated ROS generation are discussed. Moreover, cellular functions linked to physiological and pathological conditions that exhibit crosstalk between Rac1 outcomes are analyzed, while plausible roles in neuronal functions (and dysfunctions) are highlighted. Together, discussed evidence shed light on cellular mechanisms which requires Rac1 to direct either actin- and/or ROS-related events, helping to understand crucial roles of Rac1 dual functionality.
小分子 RhoGTPase Rac1 涉及到与肌动蛋白细胞骨架重排相关的各种事件。值得注意的是，另一个与肌动蛋白调节完全不同的事件也具有相同的重要性；Rac1 通过 NADPH 氧化酶（NOX）介导的活性氧（ROS）的产生。每种结果都涉及不同的 Rac1 下游效应物；一方面，与肌动蛋白细胞骨架相关的事件需要 Rac1 与 WAVEs 蛋白和 PAKs 结合，最终促进肌动蛋白分支和周转，另一方面，NOX 衍生的 ROS 产生需要活性 Rac1 与 NOX 的细胞质激活剂结合。Rac1 介导的信号如何最终促进与肌动蛋白相关的事件、NOX 衍生的 ROS 或两者都知之甚少。Rac1 的调节剂，包括支架蛋白，已知对其功能具有严格的控制作用。因此，讨论了导致肌动蛋白重塑和 NOX 介导的 ROS 生成的 Rac1 调节事件的证据。此外，还分析了与生理和病理条件相关的细胞功能，这些条件表现出 Rac1 结果之间的串扰，同时强调了在神经元功能（及其功能障碍）中的可能作用。综上所述，所讨论的证据阐明了细胞机制，该机制需要 Rac1 来指导肌动蛋白和/或 ROS 相关事件，有助于理解 Rac1 双重功能的关键作用。
