Redox-modulated SNX25 as a novel regulator of GPCR-G protein signaling from endosomes

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_i/q and their ability to bind GDP-bound (inactive form) Gα_i/q. As a result, SNX25 recruits these RGS proteins to endosomes, leading to the termination of endosomal Gα_i/q signaling. Furthermore, we have found that the SNX25/RGS complex also exerts a negative regulatory effect on Gα_i/q signaling from the plasma membrane. This is achieved by recruiting Gα_i/q 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_i/q signaling, thereby uncovering a novel mechanism for terminating Gα_i/q signaling from endosomes. Importantly, this study expands our understanding of the regulation of GPCR-Gα_i/q signaling beyond the plasma membrane.