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.
This family belongs to the Retromer Superfamily.
References:
Bhatia, V.K., K.L. Madsen, P.Y. Bolinger, A. Kunding, P. Hedegård, U. Gether, and D. Stamou. (2009). Amphipathic motifs in BAR domains are essential for membrane curvature sensing. EMBO. J. 28: 3303-3314.
Chandra, M., B.M. Collins, and L.P. Jackson. (2022). Biochemical basis for an interaction between SNX27 and the flexible SNX1 N-terminus. Adv Biol Regul 83: 100842.
Cozier, G.E., J. Carlton, A.H. McGregor, P.A. Gleeson, R.D. Teasdale, H. Mellor, and P.J. Cullen. (2002). The phox homology (PX) domain-dependent, 3-phosphoinositide-mediated association of sorting nexin-1 with an early sorting endosomal compartment is required for its ability to regulate epidermal growth factor receptor degradation. J. Biol. Chem. 277: 48730-48736.
Ivanov, R., T. Brumbarova, A. Blum, A.M. Jantke, C. Fink-Straube, and P. Bauer. (2014). SORTING NEXIN1 is required for modulating the trafficking and stability of the Arabidopsis IRON-REGULATED TRANSPORTER1. Plant Cell 26: 1294-1307.
Kim, E., Y. Lee, H.J. Lee, J.S. Kim, B.S. Song, J.W. Huh, S.R. Lee, S.U. Kim, S.H. Kim, Y. Hong, I. Shim, and K.T. Chang. (2010). Implication of mouse Vps26b-Vps29-Vps35 retromer complex in sortilin trafficking. Biochem. Biophys. Res. Commun. 403: 167-171.
Overduin, M. and R. Bhat. (2024). Recognition and remodeling of endosomal zones by sorting nexins. Biochim. Biophys. Acta. Biomembr 1866: 184305.
Simonetti, B., J.L. Daly, and P.J. Cullen. (2023). Out of the ESCPE room: Emerging roles of endosomal SNX-BARs in receptor transport and host-pathogen interaction. Traffic 24: 234-250.
van Weering, J.R., R.B. Sessions, C.J. Traer, D.P. Kloer, V.K. Bhatia, D. Stamou, S.R. Carlsson, J.H. Hurley, and P.J. Cullen. (2012). Molecular basis for SNX-BAR-mediated assembly of distinct endosomal sorting tubules. EMBO. J. 31: 4466-4480.
Examples:
TC#	Name	Organismal Type	Example
8.A.194.1.1	*Sorting nextin 1 of 522 aas and possibly one TMS at residue 400. It targets Irt1 (TC# 2.A.5.1.2) to the plasma membrane (Ivanov et al.* 2014).**		SNX1 of Homo sapiens

8.A.194.1.2	Sorting nexin-7-like protein, SNX7, of 477 aas and possibly 1 TMS.		SNX7 of Acromyrmex echinatior

8.A.194.1.3	Sorting nexin-11 isoform X2, SNX11X2, of 624 aas and 3 N-terminal TMSs.		SNX11X2 of Xiphophorus hellerii

8.A.194.1.4	Uncharacterized nexin protein of 698 aas and possibly 2 TMSs, one N-terminal and one at about residue 470.		UP of Suillus hirtellus

8.A.194.1.5	Uncharacterized nexin homologue of 456 aas and 0 TMSs.		*UP of Brachypodium distachyon* (stiff brome)**

8.A.194.1.6	Uncharacterized protein of 634 aas and 0 TMSs.		UP of Tuber indicum

8.A.194.1.7	Sorting nexin-8 isoform X1, SNX8X1, of 521 aas and possibly 2 TMSs, one near the N- terminus and one at the C-terminus.		SNX8X1 of Sphaeramia orbicularis

8.A.194.1.8	Uncharacterized protein of 840 aas and 0 TMSs.		UP of Edaphochlamys debaryana