The George Washington University, Washington, DC 20052, USA.
Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA.
Int J Mol Sci. 2021 Feb 26;22(5):2319. doi: 10.3390/ijms22052319.
The SNX-PXA-RGS-PXC subfamily of sorting nexins (SNXs) belongs to the superfamily of SNX proteins. SNXs are characterized by the presence of a common phox-homology (PX) domain, along with other functional domains that play versatile roles in cellular signaling and membrane trafficking. In addition to the PX domain, the SNX-PXA-RGS-PXC subfamily, except for SNX19, contains a unique RGS (regulators of G protein signaling) domain that serves as GTPase activating proteins (GAPs), which accelerates GTP hydrolysis on the G protein α subunit, resulting in termination of G protein-coupled receptor (GPCR) signaling. Moreover, the PX domain selectively interacts with phosphatidylinositol-3-phosphate and other phosphoinositides found in endosomal membranes, while also associating with various intracellular proteins. Although SNX19 lacks an RGS domain, all members of the SNX-PXA-RGS-PXC subfamily serve as dual regulators of receptor cargo signaling and endosomal trafficking. This review discusses the known and proposed functions of the SNX-PXA-RGS-PXC subfamily and how it participates in receptor signaling (both GPCR and non-GPCR) and endosomal-based membrane trafficking. Furthermore, we discuss the difference of this subfamily of SNXs from other subfamilies, such as SNX-BAR nexins (Bin-Amphiphysin-Rvs) that are associated with retromer or other retrieval complexes for the regulation of receptor signaling and membrane trafficking. Emerging evidence has shown that the dysregulation and malfunction of this subfamily of sorting nexins lead to various pathophysiological processes and disorders, including hypertension.
分选连接蛋白（SNX）的 SNX-PXA-RGS-PXC 亚家族属于 SNX 蛋白超家族。SNX 蛋白的特征是存在一个共同的 PHX 同源（PX）结构域，以及其他在细胞信号转导和膜运输中发挥多种作用的功能域。除了 PX 结构域外，SNX-PXA-RGS-PXC 亚家族（除了 SNX19）还包含一个独特的 RGS（G 蛋白信号调节因子）结构域，作为 GTP 酶激活蛋白（GAP），加速 G 蛋白α亚基上的 GTP 水解，从而终止 G 蛋白偶联受体（GPCR）信号。此外，PX 结构域选择性地与内体膜中发现的磷酸肌醇-3-磷酸和其他磷酸肌醇相互作用，同时也与各种细胞内蛋白结合。虽然 SNX19 缺乏 RGS 结构域，但 SNX-PXA-RGS-PXC 亚家族的所有成员都作为受体货物信号和内体运输的双重调节因子。本综述讨论了已知和提出的 SNX-PXA-RGS-PXC 亚家族的功能，以及它如何参与受体信号（包括 GPCR 和非 GPCR）和基于内体的膜运输。此外，我们讨论了这个 SNX 亚家族与其他亚家族（如与 retromer 或其他回收复合物相关的 SNX-BAR 连接蛋白（Bin-Amphiphysin-Rvs））的区别，这些亚家族与受体信号和膜运输的调节有关。新出现的证据表明，这个分选连接蛋白亚家族的失调和功能障碍导致了各种病理生理过程和疾病，包括高血压。
