GPCR-G protein signaling from endosomes plays a crucial role in various physiological and pathological processes. However, the mechanism by which endosomal G protein signaling is terminated remains largely unknown. In this study, we aimed to investigate the regulatory mechanisms involved in terminating the signaling of Gα subunits from endosomes. Through structural analysis and cell-based assays, we have discovered that SNX25, a protein that targets endosomes via its PXA or PXC domain, interacts with regulator of G protein signaling (RGS) proteins (including RGS2, RGS4, RGS8, and RGS17) in a redox-regulated manner. The interaction between SNX25 and these RGS proteins enhances their GTPase-accelerating activity towards Gα and their ability to bind GDP-bound (inactive form) Gα. As a result, SNX25 recruits these RGS proteins to endosomes, leading to the termination of endosomal Gα signaling. Furthermore, we have found that the SNX25/RGS complex also exerts a negative regulatory effect on Gα signaling from the plasma membrane. This is achieved by recruiting Gα to endosomes and preventing its activation on the plasma membrane. Our findings shed light on the previously unknown role of redox-modulated SNX25 in inhibiting Gα signaling, thereby uncovering a novel mechanism for terminating Gα signaling from endosomes. Importantly, this study expands our understanding of the regulation of GPCR-Gα signaling beyond the plasma membrane.

中文翻译：

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氧化还原调节的 SNX25 作为内体 GPCR-G 蛋白信号传导的新型调节剂


来自内体的 GPCR-G 蛋白信号在各种生理和病理过程中发挥着至关重要的作用。然而，内体 G 蛋白信号传导终止的机制仍然很大程度上未知。在本研究中，我们旨在研究终止内体 Gα 亚基信号传导所涉及的调控机制。通过结构分析和基于细胞的测定，我们发现 SNX25（一种通过其 PXA 或 PXC 结构域靶向内涵体的蛋白质）与 G 蛋白信号传导 (RGS) 蛋白（包括 RGS2、RGS4、RGS8 和 RGS17）的调节因子相互作用氧化还原调节方式。 SNX25 和这些 RGS 蛋白之间的相互作用增强了它们对 Gα 的 GTP 酶加速活性以及它们结合 GDP 结合（非活性形式）Gα 的能力。结果，SNX25 将这些 RGS 蛋白招募到内体，导致内体 Gα 信号传导终止。此外，我们发现SNX25/RGS复合物还对质膜的Gα信号传导产生负调节作用。这是通过将 Gα 募集到核内体并防止其在质膜上激活来实现的。我们的研究结果揭示了氧化还原调节的 SNX25 在抑制 Gα 信号传导中的先前未知的作用，从而揭示了一种终止内体 Gα 信号传导的新机制。重要的是，这项研究扩展了我们对质膜外 GPCR-Gα 信号传导调节的理解。