{"gene":"SNX1","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":1996,"finding":"SNX1 binds directly to a region of the EGFR cytoplasmic tail containing the lysosomal targeting code, and overexpression of SNX1 decreases cell-surface EGFR by enhancing rates of constitutive and ligand-induced receptor degradation.","method":"Co-immunoprecipitation/binding assay (SNX1 identified via interaction with EGFR tail); overexpression functional assay measuring EGFR surface levels and degradation rates","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, binding and overexpression assay, replicated directionally by multiple later studies","pmids":["8638121"],"is_preprint":false},{"year":1997,"finding":"Yeast Vps5p (ortholog of SNX1) localizes to an endosome-like prevacuolar compartment and is required for retrieval of late-Golgi membrane proteins (A-ALP, Kex2p) and the CPY sorting receptor Vps10p from the prevacuolar/endosomal compartment back to the late Golgi; loss of Vps5p causes mislocalization of these proteins to the vacuole.","method":"Genetic null mutant analysis, subcellular fractionation, immunofluorescence microscopy, vacuolar protein sorting assays","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetics, fractionation, immunofluorescence, functional sorting assays) in yeast ortholog establishing endosome-to-Golgi retrieval function","pmids":["9175702"],"is_preprint":false},{"year":2004,"finding":"SNX1 binds the C-terminal intracellular tails of multiple 7TM/GPCRs (at least 10 of 59 tested), including the delta-opioid receptor and virally encoded US28, with nanomolar affinity confirmed by surface plasmon resonance; an extended epitope on the NK1 receptor tail mediates binding to SNX1.","method":"GST pull-down with a library of 59 GPCR C-terminal tail fusion proteins; surface plasmon resonance binding kinetics; NK1 receptor truncation mapping","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic pull-down plus SPR kinetics, single lab, multiple receptor tails tested","pmids":["15452121"],"is_preprint":false},{"year":2006,"finding":"Endogenous SNX1 is required for lysosomal sorting and degradation of activated PAR1 (a GPCR) in a pathway that is independent of retromer (Vps26/Vps35), Hrs, and Tsg101; SNX2, which dimerizes with SNX1, is not essential for PAR1 degradation but can disrupt endosomal SNX1 localization when overexpressed.","method":"siRNA depletion of SNX1 (and retromer subunits, Hrs, Tsg101) in HeLa cells; siRNA-resistant SNX1 rescue construct; agonist-induced PAR1 degradation assays; genetic epistasis by combinatorial knockdowns","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA depletion with rescue construct, epistasis knockdowns of multiple pathway components, clean degradation readout, single rigorous study with multiple orthogonal controls","pmids":["16407403"],"is_preprint":false},{"year":2006,"finding":"The mammalian retromer complex consists of two autonomously assembling subcomplexes: an obligate Vps26-Vps29-Vps35 heterotrimer and a SNX1/SNX2 alternative heterodimer or homodimer. Association of Vps26-Vps29-Vps35 with endosomes requires the presence of either SNX1 or SNX2, whereas SNX1/SNX2 can be recruited to endosomes independently of Vps26-Vps29-Vps35. Either SNX1 or SNX2 is essential for retrieval of CI-MPR to the TGN.","method":"Biochemical fractionation, co-immunoprecipitation, siRNA depletion of SNX1, SNX2, or both in HeLa cells; CI-MPR trafficking assays","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA with functional rescue, multiple orthogonal methods, well-replicated by subsequent studies","pmids":["17101778"],"is_preprint":false},{"year":2007,"finding":"SNX1 depletion by siRNA causes increased intracellular accumulation and turnover of EGF-induced internalized E-cadherin, and impairs its recycling back to the plasma membrane, demonstrating that SNX1 retrieves E-cadherin from a degradative endosomal pathway to promote recycling.","method":"siRNA depletion of SNX1 in MCF-7 cells; immunofluorescence colocalization of E-cadherin with SNX1-positive endosomes; E-cadherin recycling and degradation assays","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with functional trafficking readout, single lab, two orthogonal assays (degradation and recycling)","pmids":["17502486"],"is_preprint":false},{"year":2007,"finding":"SNX1-positive buds and vesicles on early endosomes constitute distinct endosome-to-TGN transport carriers (ETCs) that mediate recycling of both MPRs and sortilin; SNX1 depletion by siRNA decreases sortilin in the TGN and increases its lysosomal degradation.","method":"Quantitative immuno-electron microscopy; siRNA depletion of SNX1; 3D electron tomography of ETC structures in HepG2 cells","journal":"Traffic","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative immuno-EM and 3D electron tomography provide structural localization, combined with siRNA functional assay, single lab but multiple orthogonal methods","pmids":["18088323"],"is_preprint":false},{"year":2007,"finding":"EHD1 associates with retromer in vivo and is required to stabilize SNX1-positive endosomal tubules; loss of EHD1 by RNAi destabilizes SNX1 tubules and inhibits endosome-to-Golgi CI-MPR retrieval. A dominant-negative P-loop mutation in EHD1 disrupts retromer localization.","method":"Comparative proteomics of retromer-deficient vs. wild-type endosomal fractions; co-immunoprecipitation of EHD1 with retromer; RNAi knockdown of EHD1; dominant-negative EHD1 P-loop mutant; CI-MPR trafficking assay","journal":"Traffic","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RNAi functional assay, dominant-negative mutagenesis, single lab","pmids":["17868075"],"is_preprint":false},{"year":2007,"finding":"SNX1 and SNX2 are each required for efficient Shiga toxin retrograde transport from endosomes to the trans-Golgi network; combined depletion of both gives ~80% inhibition, indicating partial redundancy.","method":"siRNA depletion of SNX1 and/or SNX2 in Vero cells; Shiga toxin transport to TGN assay","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with functional toxin transport readout, single lab, combinatorial knockdown establishing redundancy","pmids":["17498660"],"is_preprint":false},{"year":2017,"finding":"SNX-1 and its binding partner RME-8 oppose the assembly of HGRS-1/ESCRT-0 degradative microdomains on endosomes; loss of SNX-1 increases endosomal coverage and membrane binding of HGRS-1. This directionality is specific to SNX-1 and RME-8, as loss of other retromer components (SNX-3, VPS-35) does not affect HGRS-1 microdomains. Depletion of SNX1 and SNX2 in HeLa cells also leads to greater overlap of Rme-8 and Hrs on endosomes.","method":"C. elegans snx-1 null and rme-8 temperature-sensitive mutants; in vivo live imaging of endosomal microdomains in coelomocytes; HGRS-1 membrane fractionation; SNX1/SNX2 siRNA knockdown in HeLa cells","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null mutants plus fractionation plus live imaging, conserved result validated in mammalian cells, multiple orthogonal methods","pmids":["28053230"],"is_preprint":false},{"year":2018,"finding":"SNX1 and SNX6 form a stable 1:1 heterodimer in solution; co-expression of both subunits is required for successful production of the complex, establishing the biochemical basis of the heterodimer.","method":"Recombinant co-expression and purification; solution biochemistry (size-exclusion chromatography/analytical ultracentrifugation implied by stoichiometry determination)","journal":"Protein Expression and Purification","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reconstitution of heterodimer, single lab, limited functional follow-up reported in abstract","pmids":["29908913"],"is_preprint":false},{"year":2021,"finding":"Cryo-electron microscopy reveals that SNX1 assembles into a protein lattice of helical rows of SNX1 dimers wrapped around tubular membranes in a crosslinked fashion, providing a molecular explanation for how SNX1 deforms membranes to generate transport carriers. Comparison with the retromer-SNX coat complex reveals how retromer affects the molecular organization of SNX1 within the coat.","method":"Cryo-electron microscopy (cryo-EM) structural determination of SNX1 on tubular membranes; structural comparison with retromer-SNX coat complex","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with functional domain interpretation, single rigorous study with high-resolution structural data","pmids":["33658379"],"is_preprint":false},{"year":2021,"finding":"SNX27 directly interacts with the flexible N-terminus of SNX1 through a DxF motif; the SNX27 FERM domain mediates binding to the SNX1 N-terminus with ~10 μM affinity; mutation of either DxF sequence in SNX1 abolishes measurable binding to SNX27.","method":"Pulldown assays with purified proteins; isothermal titration calorimetry (ITC); SNX1 N-terminal truncation and DxF mutant mapping; SNX27 domain truncation analysis","journal":"Advances in Biological Regulation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins, calorimetric quantification, mutagenesis abrogating binding, single lab but multiple orthogonal biochemical methods","pmids":["34866035"],"is_preprint":false},{"year":2021,"finding":"SNX1 co-localizes and co-immunoprecipitates with AT1R in aortic tissue; SNX1 knockout (CRISPR/Cas9) or siRNA knockdown increases AT1R protein levels and downstream calcium signaling by reducing AT1R proteasomal degradation (not lysosomal); cycloheximide chase assays confirm reduced AT1R protein turnover upon SNX1 loss, and ubiquitin-AT1R binding is decreased after SNX1 knockdown.","method":"CRISPR/Cas9 SNX1 knockout mice; siRNA knockdown in A10 cells; co-immunoprecipitation; immunofluorescence colocalization; cycloheximide chase; proteasomal/lysosomal inhibitor experiments; calcium signaling assay","journal":"Hypertension Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KO mice, siRNA, co-IP, cycloheximide chase, inhibitor experiments), single lab","pmids":["33972750"],"is_preprint":false},{"year":2022,"finding":"During starvation, SNX1 regulates the formation of endosomal tubules that tether to ER subdomains engaged in autophagosome biogenesis; this endosomal membrane tubulation toward VAPB-positive ER is regulated by a SNX1-SNX2 cooperation where SNX2 interacts with VAPB at the ER membrane.","method":"SNX1/SNX2 depletion (siRNA/KO) in mammalian cells; live-cell imaging of endosomal tubules during starvation; co-localization of SNX1 tubules with ER autophagy markers; functional autophagic response assays","journal":"Life Science Alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with functional depletion, single lab, multiple imaging and functional readouts","pmids":["36585258"],"is_preprint":false},{"year":2024,"finding":"DNAJC13 modulates SNX1 function in clathrin-dependent retromer transport in a complex with Hsc70; binding and dissociation of DNAJC13 and SNX1 is controlled by Hsc70 activity. Excess α-synuclein decreases the interaction between SNX1 and VPS35, disrupting retromer-mediated retrograde transport.","method":"Co-immunoprecipitation of DNAJC13-SNX1-Hsc70; pharmacological Hsc70 inhibition; α-synuclein overexpression with SNX1-VPS35 interaction assay; retrograde transport functional assays in PD-mimetic cell models","journal":"Cell Death Discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with multiple partners, functional transport assays in multiple PD-mimetic conditions, single lab","pmids":["38886344"],"is_preprint":false}],"current_model":"SNX1 is a PX-BAR domain sorting nexin that assembles into helical dimeric lattices on endosomal membranes to drive tubule formation; it functions as part of the retromer complex (as an interchangeable SNX1/SNX2 dimer partnered with the Vps26-Vps29-Vps35 trimer) to retrieve cargo such as CI-MPR, sortilin, Shiga toxin, and multiple GPCRs from endosomes to the TGN, while also directing select receptors (EGFR, PAR1, AT1R) toward lysosomal or proteasomal degradation; SNX1 additionally opposes ESCRT-0-mediated degradative microdomain assembly, interacts directly with SNX27 (via a DxF motif/FERM domain interface) to link to plasma membrane recycling pathways, and participates in starvation-induced endosome-ER tethering to support autophagosome biogenesis."},"narrative":{"mechanistic_narrative":"SNX1 is a sorting nexin that governs the sorting of internalized membrane cargo between endosome-to-Golgi retrieval, plasma membrane recycling, and degradative pathways [PMID:17101778, PMID:18088323]. Its core conserved function, established through the yeast ortholog Vps5p, is retrieval of cargo from the endosomal/prevacuolar compartment back to the late Golgi [PMID:9175702], and in mammals SNX1 acts as one half of an interchangeable SNX1/SNX2 dimer that, together with the obligate Vps26-Vps29-Vps35 trimer, constitutes the retromer complex; either SNX1 or SNX2 is required to recruit the trimer to endosomes and to retrieve CI-MPR and sortilin to the TGN [PMID:17101778, PMID:18088323]. Structurally, SNX1 assembles into helical rows of crosslinked dimers wrapped around tubular membranes, providing the membrane-deforming activity that generates endosome-to-TGN transport carriers [PMID:33658379], and these carriers mediate retrograde transport of cargo including Shiga toxin [PMID:17498660]. Beyond retrieval, SNX1 binds the cytoplasmic tails of multiple cargoes — the EGFR lysosomal targeting motif [PMID:8638121], at least ten GPCR tails with nanomolar affinity [PMID:15452121] — and can direct receptors to degradation: it is required for retromer-independent lysosomal sorting of activated PAR1 [PMID:16407403] and for proteasomal turnover of AT1R [PMID:33972750], while conversely retrieving E-cadherin from a degradative route to promote its recycling [PMID:17502486]. SNX1 also opposes ESCRT-0 (Hrs/HGRS-1) degradative microdomain assembly on endosomes in conjunction with RME-8 [PMID:28053230], links to plasma-membrane recycling via a direct DxF-motif interaction with the SNX27 FERM domain [PMID:34866035], and during starvation cooperates with SNX2 to form endosomal tubules that tether to VAPB-positive ER subdomains supporting autophagosome biogenesis [PMID:36585258].","teleology":[{"year":1996,"claim":"Established SNX1 as a cargo-tail-binding protein that controls receptor fate, by showing it engages the EGFR lysosomal targeting code and promotes receptor degradation.","evidence":"Co-IP/binding assay and overexpression measuring EGFR surface levels and degradation rates","pmids":["8638121"],"confidence":"Medium","gaps":["Based on overexpression rather than endogenous loss-of-function","Did not define the endosomal machinery or membrane mechanism downstream of cargo binding"]},{"year":1997,"claim":"Defined the conserved core function of the SNX1 ortholog as endosome-to-late-Golgi retrieval, framing SNX1 as a retrieval factor rather than purely a degradative router.","evidence":"Yeast Vps5p null mutant analysis with fractionation, immunofluorescence, and vacuolar sorting assays","pmids":["9175702"],"confidence":"High","gaps":["Established in yeast ortholog; mammalian cargo set not yet defined","Did not identify partner subunits of the retrieval machinery"]},{"year":2004,"claim":"Showed SNX1 binds a broad set of GPCR C-terminal tails with high affinity, generalizing its cargo-recognition role beyond EGFR to seven-transmembrane receptors.","evidence":"GST pull-down across 59 GPCR tail fusions, SPR kinetics, and NK1 receptor truncation mapping","pmids":["15452121"],"confidence":"Medium","gaps":["In vitro binding did not establish trafficking outcome for each receptor","Did not resolve which interactions retrieve versus degrade cargo"]},{"year":2006,"claim":"Resolved the architecture of mammalian retromer as a SNX1/SNX2 dimer plus a Vps26-Vps29-Vps35 trimer and established that SNX1/SNX2 recruits the trimer to endosomes for CI-MPR retrieval.","evidence":"Biochemical fractionation, reciprocal Co-IP, and combinatorial siRNA depletion with CI-MPR trafficking assays in HeLa cells","pmids":["17101778"],"confidence":"High","gaps":["Did not determine how the SNX dimer is itself targeted to the correct membrane microdomain","Interchangeability of SNX1 vs SNX2 for all cargoes not exhaustively tested"]},{"year":2006,"claim":"Demonstrated a retromer-independent degradative role for SNX1, showing endogenous SNX1 routes activated PAR1 to lysosomes without Vps26/Vps35, Hrs, or Tsg101.","evidence":"siRNA depletion with siRNA-resistant rescue and epistasis knockdowns plus agonist-induced PAR1 degradation assays","pmids":["16407403"],"confidence":"High","gaps":["Molecular machinery substituting for retromer/ESCRT in this pathway not identified","Generality of retromer-independent degradation to other GPCRs unresolved"]},{"year":2007,"claim":"Defined SNX1-positive endosome-to-TGN transport carriers as discrete structures and broadened the retrieval cargo repertoire while also showing SNX1 can rescue cargo from degradation toward recycling.","evidence":"Quantitative immuno-EM and 3D electron tomography (sortilin/MPR carriers); siRNA with E-cadherin recycling/degradation assays; Shiga toxin transport assays","pmids":["18088323","17502486","17498660"],"confidence":"High","gaps":["Did not establish how cargo is selected into versus excluded from a given carrier","Redundancy with SNX2 left some functions only partially attributable to SNX1"]},{"year":2007,"claim":"Identified EHD1 as a factor stabilizing SNX1 endosomal tubules, linking tubule integrity to retromer-dependent CI-MPR retrieval.","evidence":"Comparative endosomal proteomics, Co-IP, EHD1 RNAi, and dominant-negative P-loop mutant with CI-MPR trafficking assay","pmids":["17868075"],"confidence":"Medium","gaps":["Direct versus indirect EHD1-SNX1 contact not established","Did not resolve the mechanical step EHD1 contributes to tubule stability"]},{"year":2017,"claim":"Revealed a regulatory role for SNX1 in restricting degradative microdomains, showing SNX1/SNX-1 with RME-8 opposes ESCRT-0 (Hrs/HGRS-1) assembly on endosomes.","evidence":"C. elegans snx-1 null and rme-8 ts mutants with live imaging and membrane fractionation, confirmed by SNX1/SNX2 siRNA in HeLa cells","pmids":["28053230"],"confidence":"High","gaps":["Mechanism by which SNX1/RME-8 displaces or excludes HGRS-1 not defined","Relationship of this activity to retromer-mediated retrieval not fully mapped"]},{"year":2018,"claim":"Established the biochemical basis of a SNX1-containing BAR-domain heterodimer by reconstituting a stable 1:1 SNX1-SNX6 complex.","evidence":"Recombinant co-expression and purification with solution stoichiometry determination","pmids":["29908913"],"confidence":"Medium","gaps":["Functional consequences of the SNX1-SNX6 pairing not tested","Relationship to the SNX1/SNX2 dimer not resolved"]},{"year":2021,"claim":"Provided the structural mechanism of membrane deformation, showing SNX1 forms crosslinked helical lattices of dimers around tubular membranes and how retromer reorganizes this coat.","evidence":"Cryo-EM of SNX1 on tubular membranes with comparison to the retromer-SNX coat","pmids":["33658379"],"confidence":"High","gaps":["Did not capture cargo within the lattice","Dynamics of coat assembly and disassembly in cells not resolved"]},{"year":2021,"claim":"Connected SNX1 to plasma-membrane recycling machinery by mapping a direct DxF-motif interaction between the SNX1 N-terminus and the SNX27 FERM domain.","evidence":"Purified-protein pulldowns, ITC affinity measurement, and DxF/N-terminal mutagenesis abolishing binding","pmids":["34866035"],"confidence":"High","gaps":["Cellular cargo handed off via this interface not defined here","Modest ~10 uM affinity leaves regulation of the interaction open"]},{"year":2021,"claim":"Extended SNX1's degradative routing to proteasomal control of a GPCR, showing SNX1 loss raises AT1R levels and calcium signaling by reducing AT1R ubiquitination and proteasomal turnover.","evidence":"CRISPR KO mice and siRNA in A10 cells with Co-IP, cycloheximide chase, and proteasomal/lysosomal inhibitor experiments","pmids":["33972750"],"confidence":"Medium","gaps":["Mechanistic link between an endosomal sorting nexin and proteasomal degradation not resolved","Whether SNX1 acts directly or via an adaptor on AT1R unclear"]},{"year":2022,"claim":"Implicated SNX1 in autophagy initiation, showing starvation-induced SNX1 tubules tether to VAPB-positive ER subdomains in cooperation with SNX2 to support autophagosome biogenesis.","evidence":"SNX1/SNX2 depletion with live-cell imaging of endosomal tubules and ER autophagy markers plus autophagic response assays","pmids":["36585258"],"confidence":"Medium","gaps":["Direct SNX1 contribution distinct from SNX2-VAPB binding not isolated","How tubule-ER contact promotes autophagosome formation mechanistically not defined"]},{"year":2024,"claim":"Identified chaperone and disease-relevant regulation of SNX1, showing DNAJC13/Hsc70 controls SNX1 association in retromer transport and that excess alpha-synuclein weakens SNX1-VPS35 coupling.","evidence":"Co-IP of DNAJC13-SNX1-Hsc70, Hsc70 inhibition, and alpha-synuclein overexpression with SNX1-VPS35 interaction and retrograde transport assays in PD-mimetic models","pmids":["38886344"],"confidence":"Medium","gaps":["Causal contribution to disease pathology not established","Whether alpha-synuclein acts directly on the SNX1-VPS35 interface unresolved"]},{"year":null,"claim":"How SNX1 discriminates among retrieval, recycling, and degradative fates for a given bound cargo, and what signals switch it between these outputs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking cargo-tail recognition to fate selection","Regulatory inputs (post-translational modification, lipid signals) that direct SNX1 between pathways not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,12]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[11]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[4,6,7,11]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,6]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,4,6]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,8,11]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,13]}],"complexes":["retromer (SNX1/SNX2 + Vps26-Vps29-Vps35)","SNX1-SNX6 heterodimer","SNX1-SNX2 dimer"],"partners":["SNX2","VPS35","SNX6","SNX27","EHD1","RME-8","DNAJC13","EGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13596","full_name":"Sorting nexin-1","aliases":[],"length_aa":522,"mass_kda":59.1,"function":"Involved in several stages of intracellular trafficking. Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) or phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) (PubMed:12198132). Acts in part as component of the retromer membrane-deforming SNX-BAR subcomplex. 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) (Probable). Can sense membrane curvature and has in vitro vesicle-to-membrane remodeling activity (PubMed:19816406, PubMed:23085988). Involved in retrograde endosome-to-TGN transport of lysosomal enzyme receptors (IGF2R, M6PR and SORT1) and Shiginella dysenteria toxin stxB. Plays a role in targeting ligand-activated EGFR to the lysosomes for degradation after endocytosis from the cell surface and release from the Golgi (PubMed:12198132, PubMed:15498486, PubMed:17101778, PubMed:17550970, PubMed:18088323, PubMed:21040701). Involvement in retromer-independent endocytic trafficking of P2RY1 and lysosomal degradation of protease-activated receptor-1/F2R (PubMed:16407403, PubMed:20070609). Promotes KALRN- and RHOG-dependent but retromer-independent membrane remodeling such as lamellipodium formation; the function is dependent on GEF activity of KALRN (PubMed:20604901). Required for endocytosis of DRD5 upon agonist stimulation but not for basal receptor trafficking (PubMed:23152498)","subcellular_location":"Endosome membrane; Golgi apparatus, trans-Golgi network membrane; Early endosome membrane; Cell projection, lamellipodium","url":"https://www.uniprot.org/uniprotkb/Q13596/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX1","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":1208,"dependency_fraction":0.012417218543046357},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000028528","cell_line_id":"CID000678","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"SNX6","stoichiometry":10.0},{"gene":"SNX2","stoichiometry":10.0},{"gene":"SNX5","stoichiometry":10.0},{"gene":"PHKG2","stoichiometry":0.2},{"gene":"DNAJB11","stoichiometry":0.2},{"gene":"SDF2L1","stoichiometry":0.2},{"gene":"MECP2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000678","total_profiled":1310},"omim":[{"mim_id":"621073","title":"SORTING NEXIN 32; SNX32","url":"https://www.omim.org/entry/621073"},{"mim_id":"617278","title":"DENN DOMAIN-CONTAINING PROTEIN 5A; DENND5A","url":"https://www.omim.org/entry/617278"},{"mim_id":"615740","title":"TBC1 DOMAIN FAMILY, MEMBER 5; TBC1D5","url":"https://www.omim.org/entry/615740"},{"mim_id":"614906","title":"SORTING NEXIN 11; SNX11","url":"https://www.omim.org/entry/614906"},{"mim_id":"614905","title":"SORTING NEXIN 8; SNX8","url":"https://www.omim.org/entry/614905"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endosomes","reliability":"Enhanced"},{"location":"Lysosomes","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNX1"},"hgnc":{"alias_symbol":["SNX1A","MGC8664","HsT17379","Vps5"],"prev_symbol":[]},"alphafold":{"accession":"Q13596","domains":[{"cath_id":"3.30.1520.10","chopping":"141-280","consensus_level":"medium","plddt":87.9791,"start":141,"end":280},{"cath_id":"1.20.1270.60","chopping":"308-522","consensus_level":"medium","plddt":96.1019,"start":308,"end":522}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13596","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13596-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13596-F1-predicted_aligned_error_v6.png","plddt_mean":74.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX1","jax_strain_url":"https://www.jax.org/strain/search?query=SNX1"},"sequence":{"accession":"Q13596","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13596.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13596/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13596"}},"corpus_meta":[{"pmid":"8638121","id":"PMC_8638121","title":"Enhanced degradation of EGF receptors by a sorting nexin, SNX1.","date":"1996","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/8638121","citation_count":331,"is_preprint":false},{"pmid":"17101778","id":"PMC_17101778","title":"Interchangeable but essential functions of SNX1 and SNX2 in the association of retromer with endosomes and the trafficking of mannose 6-phosphate receptors.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17101778","citation_count":197,"is_preprint":false},{"pmid":"17502486","id":"PMC_17502486","title":"EGF induces macropinocytosis and SNX1-modulated recycling of E-cadherin.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17502486","citation_count":155,"is_preprint":false},{"pmid":"18088323","id":"PMC_18088323","title":"SNX1 defines an early endosomal recycling exit for sortilin and mannose 6-phosphate receptors.","date":"2007","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/18088323","citation_count":144,"is_preprint":false},{"pmid":"15452121","id":"PMC_15452121","title":"A library of 7TM receptor C-terminal tails. Interactions with the proposed post-endocytic sorting proteins ERM-binding phosphoprotein 50 (EBP50), N-ethylmaleimide-sensitive factor (NSF), sorting nexin 1 (SNX1), and G protein-coupled receptor-associated sorting protein (GASP).","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15452121","citation_count":139,"is_preprint":false},{"pmid":"16407403","id":"PMC_16407403","title":"An essential role for SNX1 in lysosomal sorting of protease-activated receptor-1: evidence for retromer-, Hrs-, and Tsg101-independent functions of sorting nexins.","date":"2006","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16407403","citation_count":113,"is_preprint":false},{"pmid":"17868075","id":"PMC_17868075","title":"EHD1 interacts with retromer to stabilize SNX1 tubules and facilitate endosome-to-Golgi retrieval.","date":"2007","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/17868075","citation_count":112,"is_preprint":false},{"pmid":"9175702","id":"PMC_9175702","title":"The yeast VPS5/GRD2 gene encodes a sorting nexin-1-like protein required for localizing membrane proteins to the late Golgi.","date":"1997","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/9175702","citation_count":103,"is_preprint":false},{"pmid":"23328941","id":"PMC_23328941","title":"Quantitative phosphoproteomics after auxin-stimulated lateral root induction identifies an SNX1 protein phosphorylation site required for growth.","date":"2013","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/23328941","citation_count":83,"is_preprint":false},{"pmid":"28053230","id":"PMC_28053230","title":"SNX-1 and RME-8 oppose the assembly of HGRS-1/ESCRT-0 degradative microdomains on endosomes.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28053230","citation_count":74,"is_preprint":false},{"pmid":"17498660","id":"PMC_17498660","title":"SNX1 and SNX2 mediate retrograde transport of Shiga toxin.","date":"2007","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17498660","citation_count":50,"is_preprint":false},{"pmid":"24835695","id":"PMC_24835695","title":"MiR-95 induces proliferation and chemo- or radioresistance through directly targeting sorting nexin1 (SNX1) in non-small cell lung cancer.","date":"2014","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/24835695","citation_count":40,"is_preprint":false},{"pmid":"33658379","id":"PMC_33658379","title":"Structural insights into membrane remodeling by SNX1.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33658379","citation_count":23,"is_preprint":false},{"pmid":"22859339","id":"PMC_22859339","title":"Silencing of SNX1 by siRNA stimulates the ligand-induced endocytosis of EGFR and increases EGFR phosphorylation in gefitinib-resistant human lung cancer cell lines.","date":"2012","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22859339","citation_count":19,"is_preprint":false},{"pmid":"33972750","id":"PMC_33972750","title":"Increased AT1 receptor expression mediates vasoconstriction leading to hypertension in Snx1-/- mice.","date":"2021","source":"Hypertension research : official journal of the Japanese Society of Hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/33972750","citation_count":16,"is_preprint":false},{"pmid":"36585258","id":"PMC_36585258","title":"A SNX1-SNX2-VAPB partnership regulates endosomal membrane rewiring in response to nutritional stress.","date":"2022","source":"Life science 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deficiency-induced downregulation of SNX1 inhibits ferroptosis through PPARs-ACSL1/4 axis in colorectal cancer.","date":"2025","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/40095264","citation_count":7,"is_preprint":false},{"pmid":"35582586","id":"PMC_35582586","title":"Involvement of SNX1 in regulating EGFR endocytosis in a gefitinib-resistant NSCLC cell lines.","date":"2019","source":"Cancer drug resistance (Alhambra, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/35582586","citation_count":6,"is_preprint":false},{"pmid":"38886344","id":"PMC_38886344","title":"Dysregulation of SNX1-retromer axis in pharmacogenetic models of Parkinson's disease.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38886344","citation_count":2,"is_preprint":false},{"pmid":"11410165","id":"PMC_11410165","title":"Structural and functional characterization of the human gene for sorting nexin 1 (SNX1).","date":"2001","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11410165","citation_count":1,"is_preprint":false},{"pmid":"41487280","id":"PMC_41487280","title":"SNX1 inhibits human ovarian cancer progression via regulation of the cell cycle, apoptosis and migration.","date":"2025","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41487280","citation_count":1,"is_preprint":false},{"pmid":"41206513","id":"PMC_41206513","title":"Division of labor in cargo and membrane recognition by SNX1-SNX5: Insights from multiscale modeling.","date":"2025","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/41206513","citation_count":1,"is_preprint":false},{"pmid":"19619858","id":"PMC_19619858","title":"Cloning of Aspergillus oryzae Aovps5 gene, homologous to vacuolar protein sorting associated gene VPS5 and construction of the disruptant.","date":"2009","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/19619858","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.27.650847","title":"Division of labor in cargo and membrane recognition by SNX1-SNX5: Insights from multiscale modelling","date":"2025-04-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.27.650847","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15261,"output_tokens":4359,"usd":0.055584,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12185,"output_tokens":4866,"usd":0.091287,"stage2_stop_reason":"end_turn"},"total_usd":0.146871,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"SNX1 binds directly to a region of the EGFR cytoplasmic tail containing the lysosomal targeting code, and overexpression of SNX1 decreases cell-surface EGFR by enhancing rates of constitutive and ligand-induced receptor degradation.\",\n      \"method\": \"Co-immunoprecipitation/binding assay (SNX1 identified via interaction with EGFR tail); overexpression functional assay measuring EGFR surface levels and degradation rates\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, binding and overexpression assay, replicated directionally by multiple later studies\",\n      \"pmids\": [\"8638121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Yeast Vps5p (ortholog of SNX1) localizes to an endosome-like prevacuolar compartment and is required for retrieval of late-Golgi membrane proteins (A-ALP, Kex2p) and the CPY sorting receptor Vps10p from the prevacuolar/endosomal compartment back to the late Golgi; loss of Vps5p causes mislocalization of these proteins to the vacuole.\",\n      \"method\": \"Genetic null mutant analysis, subcellular fractionation, immunofluorescence microscopy, vacuolar protein sorting assays\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetics, fractionation, immunofluorescence, functional sorting assays) in yeast ortholog establishing endosome-to-Golgi retrieval function\",\n      \"pmids\": [\"9175702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SNX1 binds the C-terminal intracellular tails of multiple 7TM/GPCRs (at least 10 of 59 tested), including the delta-opioid receptor and virally encoded US28, with nanomolar affinity confirmed by surface plasmon resonance; an extended epitope on the NK1 receptor tail mediates binding to SNX1.\",\n      \"method\": \"GST pull-down with a library of 59 GPCR C-terminal tail fusion proteins; surface plasmon resonance binding kinetics; NK1 receptor truncation mapping\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic pull-down plus SPR kinetics, single lab, multiple receptor tails tested\",\n      \"pmids\": [\"15452121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Endogenous SNX1 is required for lysosomal sorting and degradation of activated PAR1 (a GPCR) in a pathway that is independent of retromer (Vps26/Vps35), Hrs, and Tsg101; SNX2, which dimerizes with SNX1, is not essential for PAR1 degradation but can disrupt endosomal SNX1 localization when overexpressed.\",\n      \"method\": \"siRNA depletion of SNX1 (and retromer subunits, Hrs, Tsg101) in HeLa cells; siRNA-resistant SNX1 rescue construct; agonist-induced PAR1 degradation assays; genetic epistasis by combinatorial knockdowns\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA depletion with rescue construct, epistasis knockdowns of multiple pathway components, clean degradation readout, single rigorous study with multiple orthogonal controls\",\n      \"pmids\": [\"16407403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The mammalian retromer complex consists of two autonomously assembling subcomplexes: an obligate Vps26-Vps29-Vps35 heterotrimer and a SNX1/SNX2 alternative heterodimer or homodimer. Association of Vps26-Vps29-Vps35 with endosomes requires the presence of either SNX1 or SNX2, whereas SNX1/SNX2 can be recruited to endosomes independently of Vps26-Vps29-Vps35. Either SNX1 or SNX2 is essential for retrieval of CI-MPR to the TGN.\",\n      \"method\": \"Biochemical fractionation, co-immunoprecipitation, siRNA depletion of SNX1, SNX2, or both in HeLa cells; CI-MPR trafficking assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA with functional rescue, multiple orthogonal methods, well-replicated by subsequent studies\",\n      \"pmids\": [\"17101778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SNX1 depletion by siRNA causes increased intracellular accumulation and turnover of EGF-induced internalized E-cadherin, and impairs its recycling back to the plasma membrane, demonstrating that SNX1 retrieves E-cadherin from a degradative endosomal pathway to promote recycling.\",\n      \"method\": \"siRNA depletion of SNX1 in MCF-7 cells; immunofluorescence colocalization of E-cadherin with SNX1-positive endosomes; E-cadherin recycling and degradation assays\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with functional trafficking readout, single lab, two orthogonal assays (degradation and recycling)\",\n      \"pmids\": [\"17502486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SNX1-positive buds and vesicles on early endosomes constitute distinct endosome-to-TGN transport carriers (ETCs) that mediate recycling of both MPRs and sortilin; SNX1 depletion by siRNA decreases sortilin in the TGN and increases its lysosomal degradation.\",\n      \"method\": \"Quantitative immuno-electron microscopy; siRNA depletion of SNX1; 3D electron tomography of ETC structures in HepG2 cells\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative immuno-EM and 3D electron tomography provide structural localization, combined with siRNA functional assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18088323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"EHD1 associates with retromer in vivo and is required to stabilize SNX1-positive endosomal tubules; loss of EHD1 by RNAi destabilizes SNX1 tubules and inhibits endosome-to-Golgi CI-MPR retrieval. A dominant-negative P-loop mutation in EHD1 disrupts retromer localization.\",\n      \"method\": \"Comparative proteomics of retromer-deficient vs. wild-type endosomal fractions; co-immunoprecipitation of EHD1 with retromer; RNAi knockdown of EHD1; dominant-negative EHD1 P-loop mutant; CI-MPR trafficking assay\",\n      \"journal\": \"Traffic\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RNAi functional assay, dominant-negative mutagenesis, single lab\",\n      \"pmids\": [\"17868075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SNX1 and SNX2 are each required for efficient Shiga toxin retrograde transport from endosomes to the trans-Golgi network; combined depletion of both gives ~80% inhibition, indicating partial redundancy.\",\n      \"method\": \"siRNA depletion of SNX1 and/or SNX2 in Vero cells; Shiga toxin transport to TGN assay\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with functional toxin transport readout, single lab, combinatorial knockdown establishing redundancy\",\n      \"pmids\": [\"17498660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SNX-1 and its binding partner RME-8 oppose the assembly of HGRS-1/ESCRT-0 degradative microdomains on endosomes; loss of SNX-1 increases endosomal coverage and membrane binding of HGRS-1. This directionality is specific to SNX-1 and RME-8, as loss of other retromer components (SNX-3, VPS-35) does not affect HGRS-1 microdomains. Depletion of SNX1 and SNX2 in HeLa cells also leads to greater overlap of Rme-8 and Hrs on endosomes.\",\n      \"method\": \"C. elegans snx-1 null and rme-8 temperature-sensitive mutants; in vivo live imaging of endosomal microdomains in coelomocytes; HGRS-1 membrane fractionation; SNX1/SNX2 siRNA knockdown in HeLa cells\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null mutants plus fractionation plus live imaging, conserved result validated in mammalian cells, multiple orthogonal methods\",\n      \"pmids\": [\"28053230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SNX1 and SNX6 form a stable 1:1 heterodimer in solution; co-expression of both subunits is required for successful production of the complex, establishing the biochemical basis of the heterodimer.\",\n      \"method\": \"Recombinant co-expression and purification; solution biochemistry (size-exclusion chromatography/analytical ultracentrifugation implied by stoichiometry determination)\",\n      \"journal\": \"Protein Expression and Purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reconstitution of heterodimer, single lab, limited functional follow-up reported in abstract\",\n      \"pmids\": [\"29908913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-electron microscopy reveals that SNX1 assembles into a protein lattice of helical rows of SNX1 dimers wrapped around tubular membranes in a crosslinked fashion, providing a molecular explanation for how SNX1 deforms membranes to generate transport carriers. Comparison with the retromer-SNX coat complex reveals how retromer affects the molecular organization of SNX1 within the coat.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) structural determination of SNX1 on tubular membranes; structural comparison with retromer-SNX coat complex\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with functional domain interpretation, single rigorous study with high-resolution structural data\",\n      \"pmids\": [\"33658379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNX27 directly interacts with the flexible N-terminus of SNX1 through a DxF motif; the SNX27 FERM domain mediates binding to the SNX1 N-terminus with ~10 μM affinity; mutation of either DxF sequence in SNX1 abolishes measurable binding to SNX27.\",\n      \"method\": \"Pulldown assays with purified proteins; isothermal titration calorimetry (ITC); SNX1 N-terminal truncation and DxF mutant mapping; SNX27 domain truncation analysis\",\n      \"journal\": \"Advances in Biological Regulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins, calorimetric quantification, mutagenesis abrogating binding, single lab but multiple orthogonal biochemical methods\",\n      \"pmids\": [\"34866035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNX1 co-localizes and co-immunoprecipitates with AT1R in aortic tissue; SNX1 knockout (CRISPR/Cas9) or siRNA knockdown increases AT1R protein levels and downstream calcium signaling by reducing AT1R proteasomal degradation (not lysosomal); cycloheximide chase assays confirm reduced AT1R protein turnover upon SNX1 loss, and ubiquitin-AT1R binding is decreased after SNX1 knockdown.\",\n      \"method\": \"CRISPR/Cas9 SNX1 knockout mice; siRNA knockdown in A10 cells; co-immunoprecipitation; immunofluorescence colocalization; cycloheximide chase; proteasomal/lysosomal inhibitor experiments; calcium signaling assay\",\n      \"journal\": \"Hypertension Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KO mice, siRNA, co-IP, cycloheximide chase, inhibitor experiments), single lab\",\n      \"pmids\": [\"33972750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"During starvation, SNX1 regulates the formation of endosomal tubules that tether to ER subdomains engaged in autophagosome biogenesis; this endosomal membrane tubulation toward VAPB-positive ER is regulated by a SNX1-SNX2 cooperation where SNX2 interacts with VAPB at the ER membrane.\",\n      \"method\": \"SNX1/SNX2 depletion (siRNA/KO) in mammalian cells; live-cell imaging of endosomal tubules during starvation; co-localization of SNX1 tubules with ER autophagy markers; functional autophagic response assays\",\n      \"journal\": \"Life Science Alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with functional depletion, single lab, multiple imaging and functional readouts\",\n      \"pmids\": [\"36585258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DNAJC13 modulates SNX1 function in clathrin-dependent retromer transport in a complex with Hsc70; binding and dissociation of DNAJC13 and SNX1 is controlled by Hsc70 activity. Excess α-synuclein decreases the interaction between SNX1 and VPS35, disrupting retromer-mediated retrograde transport.\",\n      \"method\": \"Co-immunoprecipitation of DNAJC13-SNX1-Hsc70; pharmacological Hsc70 inhibition; α-synuclein overexpression with SNX1-VPS35 interaction assay; retrograde transport functional assays in PD-mimetic cell models\",\n      \"journal\": \"Cell Death Discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with multiple partners, functional transport assays in multiple PD-mimetic conditions, single lab\",\n      \"pmids\": [\"38886344\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNX1 is a PX-BAR domain sorting nexin that assembles into helical dimeric lattices on endosomal membranes to drive tubule formation; it functions as part of the retromer complex (as an interchangeable SNX1/SNX2 dimer partnered with the Vps26-Vps29-Vps35 trimer) to retrieve cargo such as CI-MPR, sortilin, Shiga toxin, and multiple GPCRs from endosomes to the TGN, while also directing select receptors (EGFR, PAR1, AT1R) toward lysosomal or proteasomal degradation; SNX1 additionally opposes ESCRT-0-mediated degradative microdomain assembly, interacts directly with SNX27 (via a DxF motif/FERM domain interface) to link to plasma membrane recycling pathways, and participates in starvation-induced endosome-ER tethering to support autophagosome biogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNX1 is a sorting nexin that governs the sorting of internalized membrane cargo between endosome-to-Golgi retrieval, plasma membrane recycling, and degradative pathways [#4, #6]. Its core conserved function, established through the yeast ortholog Vps5p, is retrieval of cargo from the endosomal/prevacuolar compartment back to the late Golgi [#1], and in mammals SNX1 acts as one half of an interchangeable SNX1/SNX2 dimer that, together with the obligate Vps26-Vps29-Vps35 trimer, constitutes the retromer complex; either SNX1 or SNX2 is required to recruit the trimer to endosomes and to retrieve CI-MPR and sortilin to the TGN [#4, #6]. Structurally, SNX1 assembles into helical rows of crosslinked dimers wrapped around tubular membranes, providing the membrane-deforming activity that generates endosome-to-TGN transport carriers [#11], and these carriers mediate retrograde transport of cargo including Shiga toxin [#8]. Beyond retrieval, SNX1 binds the cytoplasmic tails of multiple cargoes — the EGFR lysosomal targeting motif [#0], at least ten GPCR tails with nanomolar affinity [#2] — and can direct receptors to degradation: it is required for retromer-independent lysosomal sorting of activated PAR1 [#3] and for proteasomal turnover of AT1R [#13], while conversely retrieving E-cadherin from a degradative route to promote its recycling [#5]. SNX1 also opposes ESCRT-0 (Hrs/HGRS-1) degradative microdomain assembly on endosomes in conjunction with RME-8 [#9], links to plasma-membrane recycling via a direct DxF-motif interaction with the SNX27 FERM domain [#12], and during starvation cooperates with SNX2 to form endosomal tubules that tether to VAPB-positive ER subdomains supporting autophagosome biogenesis [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established SNX1 as a cargo-tail-binding protein that controls receptor fate, by showing it engages the EGFR lysosomal targeting code and promotes receptor degradation.\",\n      \"evidence\": \"Co-IP/binding assay and overexpression measuring EGFR surface levels and degradation rates\",\n      \"pmids\": [\"8638121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Based on overexpression rather than endogenous loss-of-function\", \"Did not define the endosomal machinery or membrane mechanism downstream of cargo binding\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the conserved core function of the SNX1 ortholog as endosome-to-late-Golgi retrieval, framing SNX1 as a retrieval factor rather than purely a degradative router.\",\n      \"evidence\": \"Yeast Vps5p null mutant analysis with fractionation, immunofluorescence, and vacuolar sorting assays\",\n      \"pmids\": [\"9175702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Established in yeast ortholog; mammalian cargo set not yet defined\", \"Did not identify partner subunits of the retrieval machinery\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed SNX1 binds a broad set of GPCR C-terminal tails with high affinity, generalizing its cargo-recognition role beyond EGFR to seven-transmembrane receptors.\",\n      \"evidence\": \"GST pull-down across 59 GPCR tail fusions, SPR kinetics, and NK1 receptor truncation mapping\",\n      \"pmids\": [\"15452121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro binding did not establish trafficking outcome for each receptor\", \"Did not resolve which interactions retrieve versus degrade cargo\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved the architecture of mammalian retromer as a SNX1/SNX2 dimer plus a Vps26-Vps29-Vps35 trimer and established that SNX1/SNX2 recruits the trimer to endosomes for CI-MPR retrieval.\",\n      \"evidence\": \"Biochemical fractionation, reciprocal Co-IP, and combinatorial siRNA depletion with CI-MPR trafficking assays in HeLa cells\",\n      \"pmids\": [\"17101778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not determine how the SNX dimer is itself targeted to the correct membrane microdomain\", \"Interchangeability of SNX1 vs SNX2 for all cargoes not exhaustively tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated a retromer-independent degradative role for SNX1, showing endogenous SNX1 routes activated PAR1 to lysosomes without Vps26/Vps35, Hrs, or Tsg101.\",\n      \"evidence\": \"siRNA depletion with siRNA-resistant rescue and epistasis knockdowns plus agonist-induced PAR1 degradation assays\",\n      \"pmids\": [\"16407403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular machinery substituting for retromer/ESCRT in this pathway not identified\", \"Generality of retromer-independent degradation to other GPCRs unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined SNX1-positive endosome-to-TGN transport carriers as discrete structures and broadened the retrieval cargo repertoire while also showing SNX1 can rescue cargo from degradation toward recycling.\",\n      \"evidence\": \"Quantitative immuno-EM and 3D electron tomography (sortilin/MPR carriers); siRNA with E-cadherin recycling/degradation assays; Shiga toxin transport assays\",\n      \"pmids\": [\"18088323\", \"17502486\", \"17498660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how cargo is selected into versus excluded from a given carrier\", \"Redundancy with SNX2 left some functions only partially attributable to SNX1\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified EHD1 as a factor stabilizing SNX1 endosomal tubules, linking tubule integrity to retromer-dependent CI-MPR retrieval.\",\n      \"evidence\": \"Comparative endosomal proteomics, Co-IP, EHD1 RNAi, and dominant-negative P-loop mutant with CI-MPR trafficking assay\",\n      \"pmids\": [\"17868075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect EHD1-SNX1 contact not established\", \"Did not resolve the mechanical step EHD1 contributes to tubule stability\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a regulatory role for SNX1 in restricting degradative microdomains, showing SNX1/SNX-1 with RME-8 opposes ESCRT-0 (Hrs/HGRS-1) assembly on endosomes.\",\n      \"evidence\": \"C. elegans snx-1 null and rme-8 ts mutants with live imaging and membrane fractionation, confirmed by SNX1/SNX2 siRNA in HeLa cells\",\n      \"pmids\": [\"28053230\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SNX1/RME-8 displaces or excludes HGRS-1 not defined\", \"Relationship of this activity to retromer-mediated retrieval not fully mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the biochemical basis of a SNX1-containing BAR-domain heterodimer by reconstituting a stable 1:1 SNX1-SNX6 complex.\",\n      \"evidence\": \"Recombinant co-expression and purification with solution stoichiometry determination\",\n      \"pmids\": [\"29908913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of the SNX1-SNX6 pairing not tested\", \"Relationship to the SNX1/SNX2 dimer not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the structural mechanism of membrane deformation, showing SNX1 forms crosslinked helical lattices of dimers around tubular membranes and how retromer reorganizes this coat.\",\n      \"evidence\": \"Cryo-EM of SNX1 on tubular membranes with comparison to the retromer-SNX coat\",\n      \"pmids\": [\"33658379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture cargo within the lattice\", \"Dynamics of coat assembly and disassembly in cells not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected SNX1 to plasma-membrane recycling machinery by mapping a direct DxF-motif interaction between the SNX1 N-terminus and the SNX27 FERM domain.\",\n      \"evidence\": \"Purified-protein pulldowns, ITC affinity measurement, and DxF/N-terminal mutagenesis abolishing binding\",\n      \"pmids\": [\"34866035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular cargo handed off via this interface not defined here\", \"Modest ~10 uM affinity leaves regulation of the interaction open\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended SNX1's degradative routing to proteasomal control of a GPCR, showing SNX1 loss raises AT1R levels and calcium signaling by reducing AT1R ubiquitination and proteasomal turnover.\",\n      \"evidence\": \"CRISPR KO mice and siRNA in A10 cells with Co-IP, cycloheximide chase, and proteasomal/lysosomal inhibitor experiments\",\n      \"pmids\": [\"33972750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between an endosomal sorting nexin and proteasomal degradation not resolved\", \"Whether SNX1 acts directly or via an adaptor on AT1R unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated SNX1 in autophagy initiation, showing starvation-induced SNX1 tubules tether to VAPB-positive ER subdomains in cooperation with SNX2 to support autophagosome biogenesis.\",\n      \"evidence\": \"SNX1/SNX2 depletion with live-cell imaging of endosomal tubules and ER autophagy markers plus autophagic response assays\",\n      \"pmids\": [\"36585258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SNX1 contribution distinct from SNX2-VAPB binding not isolated\", \"How tubule-ER contact promotes autophagosome formation mechanistically not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified chaperone and disease-relevant regulation of SNX1, showing DNAJC13/Hsc70 controls SNX1 association in retromer transport and that excess alpha-synuclein weakens SNX1-VPS35 coupling.\",\n      \"evidence\": \"Co-IP of DNAJC13-SNX1-Hsc70, Hsc70 inhibition, and alpha-synuclein overexpression with SNX1-VPS35 interaction and retrograde transport assays in PD-mimetic models\",\n      \"pmids\": [\"38886344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution to disease pathology not established\", \"Whether alpha-synuclein acts directly on the SNX1-VPS35 interface unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SNX1 discriminates among retrieval, recycling, and degradative fates for a given bound cargo, and what signals switch it between these outputs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking cargo-tail recognition to fate selection\", \"Regulatory inputs (post-translational modification, lipid signals) that direct SNX1 between pathways not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 12]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [4, 6, 7, 11]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 4, 6]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 8, 11]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 13]}\n    ],\n    \"complexes\": [\n      \"retromer (SNX1/SNX2 + Vps26-Vps29-Vps35)\",\n      \"SNX1-SNX6 heterodimer\",\n      \"SNX1-SNX2 dimer\"\n    ],\n    \"partners\": [\n      \"SNX2\",\n      \"VPS35\",\n      \"SNX6\",\n      \"SNX27\",\n      \"EHD1\",\n      \"RME-8\",\n      \"DNAJC13\",\n      \"EGFR\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}