8.A.194.  The Sorting Nexin (SNX) Family 

SNX1 and other sorting nexins are involved in several stages of intracellular trafficking. It interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) or phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) (Cozier et al. 2002). It acts as a component of the retromer membrane-deforming SNX-BAR subcomplex (TC families 9.A.3 and 9.A 63). The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX-BAR subcomplex functions to deform the donor membrane into a tubular profile called endosome-to-TGN transport carrier (ETC) and can sense membrane curvature; it has in vitro vesicle-to-membrane remodeling activity (Bhatia et al. 2009, van Weering et al. 2012). It is also involved in retrograde endosome-to-TGN transport of lysosomal enzyme receptors (IGF2R, M6PR and SORT1) and Shiginella dysenteria toxin, StxB. It plays a role in targeting ligand-activated EGFR to the lysosomes for degradation after endocytosis from the cell surface and release from the Golgi (Cozier et al. 2002, Kim et al. 2010). SNX1 interacts  with SNX27 and regulates the heavy metal transporter Irt1 (TC# 2.A.5.1.2) (Chandra et al. 2022). Sorting nexins are also found in TC families 9.A.3 and 9.A.63. They can recognize and remodel endosomal zones (Overduin and Bhat 2024).

A key sorting complex is the Endosomal SNX-BAR Sorting Complex for Promoting Exit (ESCPE-1) that catalyzes the recycling of an array of cargos to the plasma membrane and/or the trans-Golgi network. ESCPE-1 recognizes a hydrophobic-based sorting motif in numerous cargoes and orchestrates their packaging into tubular carriers that pinch off from the endosome and travel to the target organelle (Simonetti et al. 2023). A wide range of pathogens mimic this sorting motif to hijack ESCPE-1 transport to promote their invasion and survival within infected cells. In other instances, ESCPE-1 exerts restrictive functions against pathogens by limiting their replication and infection. Simonetti et al. 2023 discuss ESCPE-1 assembly and functions, with a particular focus on recent advances in the understanding of its role in membrane trafficking, cellular homeostasis and host-pathogen interaction.