International Journal of Molecular Sciences Review SNX-PXA-RGS-PXC Subfamily of SNXs in the Regulation of Receptor-Mediated Signaling and Membrane Trafficking Bibhas Amatya 1,†, Hewang Lee 2,†, Laureano D. Asico 2 , Prasad Konkalmatt 2, Ines Armando 2, Robin A. Felder 3 and Pedro A. Jose 2,3,4,* 1 The George Washington University, Washington, DC 20052, USA; [email protected] 2 Department of Medicine, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA; [email protected] (H.L.); [email protected] (L.D.A.); [email protected] (P.K.); [email protected] (I.A.) 3 Department of Pathology, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA; [email protected] 4 Department of Pharmacology/Physiology, The George Washington University School of Medicine & Health Sciences, Washington, DC 20052, USA * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: 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 traf- ficking. 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 Citation: Amatya, B.; Lee, H.; Asico, (GAPs), which accelerates GTP hydrolysis on the G protein α subunit, resulting in termination of L.D.; Konkalmatt, P.; Armando, I.; G protein-coupled receptor (GPCR) signaling. Moreover, the PX domain selectively interacts with Felder, R.A.; Jose, P.A. phosphatidylinositol-3-phosphate and other phosphoinositides found in endosomal membranes, SNX-PXA-RGS-PXC Subfamily of while also associating with various intracellular proteins. Although SNX19 lacks an RGS domain, all SNXs in the Regulation of members of the SNX-PXA-RGS-PXC subfamily serve as dual regulators of receptor cargo signaling Receptor-Mediated Signaling and and endosomal trafficking. This review discusses the known and proposed functions of the SNX- Membrane Trafficking. Int. J. Mol. Sci. PXA-RGS-PXC subfamily and how it participates in receptor signaling (both GPCR and non-GPCR) 2021, 22, 2319. https://doi.org/ and endosomal-based membrane trafficking. Furthermore, we discuss the difference of this subfamily 10.3390/ijms22052319 of SNXs from other subfamilies, such as SNX-BAR nexins (Bin-Amphiphysin-Rvs) that are associated Academic Editor: Martin Hohenegger 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 Received: 21 January 2021 of sorting nexins lead to various pathophysiological processes and disorders, including hypertension. Accepted: 22 February 2021 Published: 26 February 2021 Keywords: endosome; GPCR; receptor; RGS; signaling; SNX; trafficking Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. Receptor-mediated signaling and membrane trafficking processes are intimately inter- connected with the endosomes [1]. Internalized receptors, including G protein-coupled receptors (GPCRs) and non-GPCRs, are sorted at endosomes, from which receptors are either delivered to the lysosome for degradation, recycled back to the plasma membrane, Copyright: © 2021 by the authors. or delivered to the trans-Golgi network (TGN) and other organelles by receptor-specific Licensee MDPI, Basel, Switzerland. pathways [2,3]. Sorting nexins (SNXs) play critical roles in these processes [4]. This article is an open access article The SNX family has a phox homology (PX) domain, capable of phosphoinositide distributed under the terms and binding, which enables SNX targeting to endosomal membranes by binding to phos- conditions of the Creative Commons phatidylinositols, most commonly phosphatidylinositol 3-phosphate (PI(3)P) [5,6]. SNXs Attribution (CC BY) license (https:// are widely expressed from yeast to mammals, whose PX domain, first identified in two creativecommons.org/licenses/by/ subunits of the NADPH oxidase, p40phox and p47phox, actively engages in protein–lipid 4.0/). Int. J. Mol. Sci. 2021, 22, 2319. https://doi.org/10.3390/ijms22052319 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 17 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 17 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 17 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 17 tidylinositols, most commonly phosphatidylinositol 3-phosphate (PI(3)P) [5,6]. SNXs are Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 17 widelytidylinositols, expressed most from commonly yeast to phosphatidylinos mammals, whoseitol PX3-phosphate domain, first(PI(3) identifiedP) [5,6]. SNXs in two are subunitswidely expressedof the NADPH from yeastoxidase, to mammals,p40phox and whosep47phox PX, actively domain, engages first identifiedin protein–lipid in two tidylinositols, most commonly phosphatidylinositol 3-phosphate (PI(3)P) [5,6]. SNXs are andsubunitstidylinositols, protein–protein of the most NADPH interactionscommonly oxidase, phosphatidylinos [5,6]. p40 Tophox date,and p4710itol yeastphox 3-phosphate, actively and 33 engagesmammalian (PI(3)P) in [5,6]. protein–lipid SNXs SNXs have are widely expressed from yeast to mammals, whose PX domain, first identified in two beenandtidylinositols,widely protein–proteinidentified expressed most[5–8]. from commonly interactionsBased yeast on theirphosphatidylinosto [5,6].mammals, domain To date, architectures, whose 10itol yeast 3-phosphatePX anddomain, the 33 mammalian mammalian (PI(3)first P)identified [5,6]. SNXs SNXs SNXs are in have di- twoare Int. J. Mol. Sci. 2021, 22, 2319subunits of the NADPH oxidase, p40phox and p47phox, actively engages in protein–lipid 2 of 16 videdbeenwidelysubunits identified expressedinto of the [5–8]. fiveNADPH from Basedsubfam yeast oxidase, on toilies:their mammals, p40 domainphoxSNX-PXA-RGS-PXC, and architectures,whose p47phox PX, actively domain, the mammalian engagesSNX-FERM first identified in SNXs protein–lipid(protein inare two di- and protein–protein interactions [5,6]. To date, 10 yeast and 33 mammalian SNXs have 4.1/ezrin/radixin/moesin),videdsubunitsand protein–protein intoof the NADPHfive interactionssubfam SNX-BARoxidase,ilies: [5,6]. p40 (Bin/Amphiphysin/Rvs), phox ToSNX-PXA-RGS-PXC, anddate, p47 10phox yeast, actively and SNX-PX, 33 engages SNX-FERMmammalian and in theprotein–lipid SNXs unclassi-(protein have been identified [5–8]. Based on their domain architectures, the mammalian SNXs are di- fied4.1/ezrin/radixin/moesin),andbeen SNX protein–protein identified subfamilies [5–8]. [7,8]interactions Based (Table SNX-BAR on their1). [5,6]. (Bin/Amphiphysin/Rvs),domain To date, architectures, 10 yeast and the 33SNX-PX, mammalian mammalian and theSNXs SNXs unclassi- are have di- vided into five subfamilies: SNX-PXA-RGS-PXC, SNX-FERM (protein fiedbeenvided SNX identified andsubfamiliesinto protein–protein [5–8].five [7,8]Basedsubfam (Table on interactions their ilies:1). domain SNX-PXA-RGS-PXC, [5,6]. architectures, To date, 10 yeast the andmammalianSNX-FERM 33 mammalian SNXs (protein SNXsare di- have been 4.1/ezrin/radixin/moesin), SNX-BAR (Bin/Amphiphysin/Rvs), SNX-PX, and the unclassi- Tablevided4.1/ezrin/radixin/moesin), 1. Summaryidentifiedinto offive mammalian [5 –8].subfam Based SNX-BAR sortingilies: on their nexin (Bin/Amphiphysin/Rvs),SNX-PXA-RGS-PXC, domain (SNX) subfamilies architectures, [5–8]. SNX-PX, the SNX-FERM mammalian and the SNXsunclassi-(protein are divided fied SNX subfamilies [7,8] (Table 1). Table 1. Summaryinto five of subfamilies: mammalian SNX-PXA-RGS-PXC,sorting nexin (SNX) subfamilies SNX-FERM [5–8]. (protein 4.1/ezrin/radixin/moesin), 4.1/ezrin/radixin/moesin),fied SNX subfamilies [7,8] SNX-BAR(Table 1). (Bin/Amphiphysin/Rvs), SNX-PX,Roles in and Signaling, the unclassi- Subfamily * SNX-BARMembers (Bin/Amphiphysin/Rvs), Major Domain Architecture SNX-PX, and ** the unclassified SNX subfamilies [7,8] Tablefied SNX 1. Summary subfamilies of mammalian [7,8] (Table sorting 1). nexin (SNX) subfamilies Trafficking,[5–8]. Roles inand Signaling, Degradation SubfamilyTable 1.* Summary(Table1). ofMembers mammalian sortingMajor Domainnexin (SNX) Architecture subfamilies ** [5–8]. Trafficking,Plays important and Degradation roles in Table 1. Summary of mammalian sorting nexin (SNX) subfamilies [5–8]. Roles in Signaling, Subfamily * SNX13,Members SNX14, Major Domain Architecture ** receptorPlaysRoles important signalingin Signaling, roles and in SNX-PXA-RGS-PXCSubfamilyTable * (4) 1. SummaryMembers of mammalian Major sorting Domain nexin Architecture (SNX) subfamilies ** Trafficking, [5–8]. and Degradation SNX19,SNX13, SNX25 SNX14, membraneTrafficking,receptorRoles trafficking, in signaling and Signaling, Degradation seeand text SNX-PXA-RGS-PXCSubfamily * (4) Members Major Domain Architecture ** Plays important roles in SNX19, SNX25 membraneTrafficking,PlaysRolesfor important trafficking,in details. and Signaling, Degradation roles see Trafficking,in text Subfamily * MembersSNX13, SNX14, Major Domain Architecture ** receptor signaling and SNX-PXA-RGS-PXC (4) SNX13, SNX14, Involvedreceptor infor cargoand details.signaling Degradationloading and and SNX-PXA-RGS-PXC (4) SNX19, SNX25 membranePlays