{"gene":"SNX17","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2002,"finding":"SNX17 binds to the intracellular domain of LDL receptor family members (LDLR, VLDLR, ApoER2, LRP) via its PX domain, localizes to vesicular structures partially overlapping with EEA1- and Rab4-positive endosomes, and enhances the endocytosis rate of LDLR.","method":"Co-immunoprecipitation, subcellular fractionation/immunofluorescence colocalization, functional endocytosis assay with rhodamine-labeled LDL","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal binding shown, localization established, functional endocytosis assay, single lab but multiple orthogonal methods","pmids":["12169628"],"is_preprint":false},{"year":2008,"finding":"SNX17 recognizes the NPXY motif (N26) in the cytoplasmic tail of LRP1 and mediates its recycling from basolateral sorting endosomes; mutation of this NPXY motif traps LRP1 in the basolateral sorting endosome, establishing SNX17's role in basolateral/somatodendritic recycling.","method":"NPXY motif mutagenesis, trafficking assays in polarized MDCK cells and hippocampal neurons, colocalization by immunofluorescence","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional trafficking readout, single lab, multiple complementary approaches","pmids":["19005208"],"is_preprint":false},{"year":2012,"finding":"SNX17 binds to the membrane-distal NPXY motif in β1 and β5 integrin cytoplasmic tails via its FERM-like domain, thereby preventing lysosomal degradation of β integrins and their associated α subunits; this retrieval does not depend on the retromer complex, and SNX17 depletion impairs cell migration.","method":"SILAC-based quantitative proteomics, siRNA knockdown, lysosomal inhibitor assays, co-immunoprecipitation, cell migration assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased proteomic screen plus reciprocal Co-IP, mutagenesis of NPXY motif, lysosomal inhibitor rescue, functional migration readout, replicated across multiple integrin subunits","pmids":["22492727"],"is_preprint":false},{"year":2012,"finding":"SNX17 interacts with the HPV-16 L2 capsid protein and is essential for papillomavirus infection; this interaction is conserved across multiple PV types, indicating SNX17 is required for a conserved viral entry mechanism.","method":"Infection assays with multiple PV types, SNX17 knockdown, interaction studies with L2 protein","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional knockdown with infection readout across multiple PV types, single lab","pmids":["23115288"],"is_preprint":false},{"year":2012,"finding":"SNX17 acts as a cargo-specific adaptor that binds Jag1a and facilitates retromer-dependent recycling of the Notch ligand Jag1 to the plasma membrane in ligand-expressing cells; inhibition disrupts neurogenesis and pancreas development in zebrafish.","method":"Co-immunoprecipitation, zebrafish knockdown/rescue experiments, fluorescence localization","journal":"Cell regeneration","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — binding plus in vivo genetic epistasis (zebrafish), single lab","pmids":["25408867"],"is_preprint":false},{"year":2014,"finding":"SNX17 directly binds KRIT1 through its FERM domain recognizing the second NPXF motif of KRIT1; co-crystal structure at 3.0 Å reveals the interaction is highly similar to the SNX17-P-selectin interaction; site-directed mutagenesis confirms the NPXF2 motif as the major binding site.","method":"Co-crystal structure (3.0 Å resolution), site-directed mutagenesis, GST pulldown, binding affinity measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus in vitro pulldown, all in one rigorous study","pmids":["25059659"],"is_preprint":false},{"year":2015,"finding":"The FERM domain of SNX17 mediates binding and trafficking of TCR and LFA-1 (integrin) to the cell surface; SNX17 colocalizes with TCR at the immune synapse, and SNX17 knockdown reduces surface TCR and LFA-1 expression, TCR recycling, and T cell–APC conjugate formation.","method":"siRNA knockdown, immunofluorescence colocalization, flow cytometry for surface receptor expression, TCR recycling assay, domain truncation analysis","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — domain mapping plus multiple functional readouts, single lab","pmids":["25439"],"is_preprint":false},{"year":2015,"finding":"SNX17 FERM domain mediates binding and trafficking of TCR and LFA-1 to the T cell surface, as identified by domain truncation studies.","method":"Truncated SNX17 domain expression constructs, immunofluorescence, flow cytometry","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — domain truncation with functional trafficking readout, single lab","pmids":["25825439"],"is_preprint":false},{"year":2018,"finding":"SNX17 binds SERCA2a protein via its PX (phox-homology) domain, and SNX17 deficiency leads to lysosomal degradation of SERCA2a, intracellular Ca2+ overload, and cardiac arrhythmias; chloroquine (lysosomal inhibitor) prevents SNX17-knockdown-induced SERCA2a reduction.","method":"Co-immunoprecipitation with domain mapping, siRNA knockdown, lysosomal inhibitor rescue, Ca2+ imaging, electrocardiography in rat MI model","journal":"International journal of cardiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with domain mapping, lysosomal inhibitor rescue, in vivo model, single lab","pmids":["30025651"],"is_preprint":false},{"year":2019,"finding":"SNX17 recruits the deubiquitinating enzyme USP9X to antagonize MIB1-mediated ubiquitination and degradation of PCM1 during serum-starvation-induced ciliogenesis; SNX17 deficiency leads to enhanced degradation of both USP9X and PCM1 and disrupts ciliogenesis.","method":"Co-immunoprecipitation, siRNA knockdown, ciliogenesis assay, ubiquitination assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, functional ciliogenesis readout, single lab","pmids":["31671755"],"is_preprint":false},{"year":2019,"finding":"SNX17 facilitates endocytic sorting of the Kv1.5 potassium channel from the plasma membrane to early endosomes via its FERM domain; SNX17 heterozygous knockout rats show increased membrane Kv1.5 expression, increased IKur, shortened action potential duration, and increased AF susceptibility.","method":"SNX17 knockout rat model, patch clamp electrophysiology, optical mapping, immunostaining/confocal, truncated domain expression constructs","journal":"Circulation. Arrhythmia and electrophysiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with electrophysiology readout plus domain mapping, single lab","pmids":["30939909"],"is_preprint":false},{"year":2020,"finding":"SNX17 directly interacts with EHD1, a dynamin-like fission GTPase; EHD1 is recruited to endosomal membranes upon LRP1 internalization, SNX17 and EHD1 colocalize on endosomes, and EHD1 depletion causes enlargement of SNX17-containing endosomes, indicating EHD1 mediates fission of SNX17-labeled endosomal carriers.","method":"Co-immunoprecipitation, in vitro binding assay, surface rendering/quantification of colocalization volumes, EHD1 siRNA knockdown with endosomal morphology readout","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct in vitro interaction plus functional endosomal fission readout, single lab, two orthogonal methods","pmids":["32041776"],"is_preprint":false},{"year":2021,"finding":"SNX17 interacts with leiomodin-2 (LMOD2) via its C-terminal domain; SNX17 deficiency promotes lysosomal degradation of LMOD2, worsening DOX-induced cardiac systolic dysfunction.","method":"Co-immunoprecipitation with domain mapping, siRNA knockdown, lysosomal pathway inhibition, in vivo rat model of cardiotoxicity","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP with domain mapping plus lysosomal inhibitor rescue and in vivo model, single lab","pmids":["33933636"],"is_preprint":false},{"year":2022,"finding":"The C-terminus of SNX17 contains a type III PDZ-binding motif that binds PDLIM family proteins; the co-crystal structure of the PDLIM7 PDZ domain with the SNX17 C-terminus reveals an unconventional perpendicular peptide interaction mediated by electrostatic contacts and a conserved proline-containing loop in PDLIM proteins; the C-terminus of SNX17 is also sufficient for Commander complex interaction.","method":"Proteomics, co-crystal structure determination, mutagenesis, biophysical binding assays","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus proteomics plus mutagenesis, rigorous multi-method single study","pmids":["36302387"],"is_preprint":false},{"year":2023,"finding":"SNX17 pathway (SNX17-Retriever-CCC-WASH) is required in hippocampal neurons for maintenance of excitatory synapses and structural plasticity during chemical LTP; cLTP drives SNX17 recruitment to synapses in a manner requiring NMDAR activation, CaMKII signaling, Retriever binding, and PI(3)P; SNX17 partly mediates LTP effects through regulation of β1-integrin surface expression.","method":"siRNA knockdown in cultured hippocampal neurons, chemical LTP induction, immunofluorescence, spine morphology analysis, surface receptor quantification","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown with multiple functional and molecular readouts in neurons, pathway epistasis, single lab","pmids":["37141105"],"is_preprint":false},{"year":2023,"finding":"SNX17 interacts with p140Cap (a SRC kinase inhibitor/actin regulator) as identified by GST pulldown and interactome analysis; this interaction is required for dendritic spine maturation, and Snx17 haploinsufficiency in mice impairs synaptic transmission and spine maturation.","method":"GST pulldown, interactome/proteomic analysis, Snx17 heterozygous knockout mice, spine morphology, electrophysiology","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct pulldown interaction plus in vivo KO phenotype, single lab","pmids":["37704928"],"is_preprint":false},{"year":2024,"finding":"SNX17 directly interacts with Retriever through its C-terminal region binding to the VPS35L/VPS26C interface; this interaction is enhanced when SNX17 is bound to cargo (due to disruption of an intramolecular autoinhibitory interaction between the C-terminal region and the cargo-binding pocket); PI(3)P binding by SNX17 also promotes Retriever recruitment independently of cargo.","method":"Biophysical assays (binding measurements), structural model-guided mutagenesis, recombinant protein reconstitution with liposomes","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with liposomes, structural modeling, mutagenesis, and biophysical quantification in a single rigorous study","pmids":["39653850"],"is_preprint":false},{"year":2024,"finding":"SNX17 controls antigen internalisation, integrin recycling, actin cytoskeleton organization, and phagosomal maturation in dendritic cells; SNX17 silencing impairs fluid-phase endocytosis, phagocytosis, and T. gondii invasion, and disrupts cross-presentation.","method":"siRNA knockdown in dendritic cells, functional endocytosis/phagocytosis assays, integrin recycling assays, actin staining, cross-presentation assay","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — knockdown with multiple functional readouts, single lab","pmids":["39559950"],"is_preprint":false},{"year":2025,"finding":"Phosphorylation of SNX17 at serine 38 (Ser38) within the PX domain disrupts SNX17 binding to PI(3)P, impairs its association with early endosomal membranes, inactivates SNX17-dependent cargo recycling, and is part of an autoinhibitory mechanism regulating cargo binding.","method":"Phosphomimetic/phosphodead mutagenesis, PI(3)P binding assays, endosomal localization assays, cargo recycling assays in cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with multiple functional readouts (lipid binding, localization, cargo recycling), single lab","pmids":["40349777"],"is_preprint":false},{"year":2025,"finding":"Acidic pH induces a conformational change in the LDLR extracellular domain that promotes interaction between LDLR intracellular domain and SNX17; PCSK9 prevents this acidic pH-induced conformational change, thereby blocking SNX17-LDLR interaction and diverting LDLR to lysosomal degradation; SNX17 knockdown abolishes LDLR recycling and PCSK9-mediated LDLR degradation.","method":"SNX17 knockdown in cells and Ldlr KO mice, in vitro and in vivo approaches, conformational change analysis, co-immunoprecipitation, LDLR recycling assays","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo KO models, multiple orthogonal methods, mechanistic epistasis (SNX17 KD abolishes PCSK9 effect), replicated across cell and animal systems","pmids":["40071387"],"is_preprint":false},{"year":2025,"finding":"SNX17 directly interacts with STAT3 and promotes STAT3 phosphorylation in a retromer-dependent manner; the SNX17-retromer complex acts as a platform for IL-6-induced STAT3 activation, leading to c-Myc upregulation and enhanced mitochondrial OXPHOS.","method":"Co-immunoprecipitation, STAT3 inhibitor treatment, STAT3 knockdown, retromer knockdown, OXPHOS measurement","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for direct interaction claim, limited mechanistic validation of direct versus indirect STAT3 activation, single lab","pmids":["40303303"],"is_preprint":false},{"year":2025,"finding":"SNX17 interacts with the C-terminus of NHE3 (Na+/H+ exchanger 3) via an NPxY motif; mutation of the distal NPxY motif in NHE3 disrupts this interaction, leading to reduced NHE3 expression and increased degradation; SNX17 knockdown reduces NHE3 activity and stability.","method":"GST pulldown with NPxY motif mutagenesis, siRNA knockdown, NHE3 activity assay, degradation assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct pulldown with mutagenesis confirming binding site plus functional stability readout, single lab, preprint","pmids":[],"is_preprint":true},{"year":2025,"finding":"WIPI2 (a PROPPIN) integrates into Retriever-dependent coat complexes by interacting with both the Commander subunit CCDC93 and SNX17, forming the CROP2 complex; CROP2 is required for endosomal recycling of β1-integrin but not for CROP (Retromer)-dependent cargos.","method":"Co-immunoprecipitation, functional recycling assays, genetic depletion of WIPI2","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — binding interaction plus pathway-selective cargo recycling assay, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"SNX17-Commander and RAB32-LRMDA-Commander assemblies are mutually exclusive; LRMDA and SNX17 share a common mechanism of Commander association; SNX17-Commander mediates cell surface recycling while RAB32-LRMDA-Commander mediates melanosome biogenesis in melanocytes.","method":"Unbiased proteomics, recombinant protein reconstitution, computational modelling, functional assays in human melanocytes","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — recombinant reconstitution plus proteomics plus functional cellular assays, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"PI(3)P synthesis during chemical LTP drives coordinate recruitment of both the SNX17-Retriever and SNX27-Retromer pathways to endosomes and synaptic sites; preventing PI(3)P synthesis blocks SNX17 synaptic recruitment, decreases cargo recycling, and blocks LTP in cultured neurons and hippocampal slices.","method":"PI(3)P synthesis inhibition, live imaging, chemical LTP in hippocampal neurons and slices, cargo recycling assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus functional LTP readout in neurons and slices, single lab","pmids":["40920104"],"is_preprint":false},{"year":2025,"finding":"SNX17 promotes lysosomal degradation of VEGFR; in the absence of SNX17, VEGFR accumulates in early endosomes with prolonged activation, promoting angiogenesis; SNX17 knockdown in hindlimb ischemia mice increases blood flow and limb salvage.","method":"SNX17 knockdown in cells and hindlimb ischemia mouse model, endosomal localization assays, angiogenesis assays","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vivo KO with functional angiogenesis readout plus mechanistic endosomal localization data, single lab","pmids":["40412610"],"is_preprint":false},{"year":2026,"finding":"OCIAD2 binds SNX17 and enhances its association with integrin β1, promoting integrin β1 recycling to lipid raft-enriched plasma membrane regions and preventing its lysosomal degradation; this sustains FAK-PI3K-AKT-mTOR signaling.","method":"Co-immunoprecipitation with mass spectrometry, siRNA knockdown, recycling and degradation assays, lipid raft fractionation","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP/MS plus functional recycling/degradation assays, single lab","pmids":["41655222"],"is_preprint":false}],"current_model":"SNX17 is a FERM-domain- and PX-domain-containing endosomal sorting adaptor that localizes to early/sorting endosomes via PI(3)P binding through its PX domain (regulated by Ser38 phosphorylation), directly recognizes NPX(Y/F) motifs in cytoplasmic tails of transmembrane cargo proteins (integrins, LDL receptor family members, Kv1.5, NHE3, KRIT1, and others) through its FERM domain, recruits the Retriever complex (via its C-terminal region binding VPS35L/VPS26C) and the EHD1 fission machinery to mediate endosomal recycling of cargo to the plasma membrane, operates together with the Commander/CCC/WASH complex, and thereby prevents lysosomal degradation of its cargos; its activity is autoinhibited by an intramolecular C-terminal/cargo-pocket interaction that is relieved upon cargo and PI(3)P binding, and the pathway is required for integrin-dependent cell migration, T cell activation, synaptic plasticity, and LDLR recycling (the latter being blocked by PCSK9)."},"narrative":{"mechanistic_narrative":"SNX17 is an endosomal sorting adaptor that recognizes NPX(Y/F) motifs in the cytoplasmic tails of transmembrane cargo and retrieves them from the degradative pathway for recycling back to the plasma membrane [PMID:22492727, PMID:25059659]. It engages a broad cargo set through distinct domains: its FERM-like domain binds the membrane-distal NPXY/NPXF motifs of β1/β5 integrins, KRIT1, and NHE3 [PMID:22492727, PMID:25059659], while its PX domain mediates association with LDL receptor family members and anchors SNX17 to PI(3)P-positive early/sorting endosomes [PMID:12169628, PMID:40349777]. Cargo capture protects substrates from lysosomal degradation, as shown for integrins [PMID:22492727], SERCA2a [PMID:30025651], and LDLR [PMID:40071387], and is the basis for SNX17's role in integrin-dependent cell migration [PMID:22492727]. SNX17 executes recycling by recruiting the Retriever complex through its C-terminal region binding the VPS35L/VPS26C interface, operating together with the Commander/CCC and WASH machinery, and by recruiting the EHD1 fission GTPase to bud SNX17-coated carriers [PMID:32041776, PMID:36302387, PMID:39653850]. Its activity is autoinhibited by an intramolecular contact between the C-terminal region and the cargo-binding pocket that is relieved upon cargo and PI(3)P binding, and cargo recycling is further gated by Ser38 phosphorylation in the PX domain that abolishes PI(3)P binding [PMID:39653850, PMID:40349777]. Through this sorting function SNX17 supports T cell receptor and LFA-1 surface delivery and immune synapse formation [PMID:25439], antigen processing and cross-presentation in dendritic cells [PMID:39559950], and synaptic structural plasticity during LTP via β1-integrin recycling [PMID:37141105, PMID:40920104]. In lipoprotein metabolism, SNX17 binds an acidic-pH-induced conformation of the LDLR tail to recycle the receptor, a step that PCSK9 blocks to divert LDLR to lysosomal degradation [PMID:40071387].","teleology":[{"year":2002,"claim":"Established SNX17 as a direct binder of LDL receptor family cytoplasmic domains and an endosomal protein influencing receptor endocytosis, opening the question of how it sorts membrane cargo.","evidence":"Co-IP, fractionation/colocalization with EEA1 and Rab4, and LDL endocytosis assays","pmids":["12169628"],"confidence":"Medium","gaps":["Binding ascribed to PX domain rather than later-defined FERM cargo pocket","No recycling machinery identified","Single cargo family tested"]},{"year":2008,"claim":"Defined the NPXY motif as the cargo recognition signal and placed SNX17 in basolateral/somatodendritic recycling of LRP1.","evidence":"NPXY mutagenesis with trafficking readouts in polarized MDCK cells and neurons","pmids":["19005208"],"confidence":"Medium","gaps":["Domain responsible for NPXY recognition not yet mapped","Downstream coat/fission machinery unknown"]},{"year":2012,"claim":"Showed SNX17 retrieves β integrins from lysosomal degradation via FERM-domain NPXY recognition independent of retromer, linking the adaptor to cell migration and broadening its cargo repertoire to integrins and viral entry.","evidence":"SILAC proteomics, NPXY mutagenesis, lysosomal inhibitor rescue, migration assays, and PV infection knockdown studies","pmids":["22492727","23115288","25408867"],"confidence":"High","gaps":["Identity of the recycling effector complex not yet defined","Retromer-independence left open which machinery substitutes"]},{"year":2014,"claim":"Provided atomic-resolution definition of FERM-domain NPXF cargo recognition through the SNX17-KRIT1 co-crystal structure.","evidence":"3.0 Å co-crystal structure, GST pulldown, site-directed mutagenesis, affinity measurements","pmids":["25059659"],"confidence":"High","gaps":["Structure captures cargo binding but not autoinhibited or membrane-bound states","No coat complex in the structure"]},{"year":2015,"claim":"Extended SNX17 cargo handling to immune receptors, showing FERM-dependent surface delivery of TCR and LFA-1 underlies T cell activation.","evidence":"Domain truncation, siRNA knockdown, flow cytometry surface quantification, TCR recycling and conjugate assays","pmids":["25825439"],"confidence":"Medium","gaps":["Recycling effector machinery not defined in T cells","Direct vs indirect TCR binding not fully resolved"]},{"year":2018,"claim":"Demonstrated that SNX17 loss drives lysosomal degradation of SERCA2a, with physiological consequences for cardiac Ca2+ handling and arrhythmia.","evidence":"Co-IP domain mapping, lysosomal inhibitor rescue, Ca2+ imaging, ECG in a rat MI model","pmids":["30025651"],"confidence":"Medium","gaps":["PX-domain-mediated binding to an intracellular cargo differs from NPXY paradigm","Recycling versus stabilization mechanism unclear"]},{"year":2019,"claim":"Identified EHD1 as the fission GTPase that resolves SNX17 carriers and showed SNX17 sorts Kv1.5, connecting the adaptor to endosomal membrane budding and ion channel surface levels.","evidence":"In vitro EHD1 binding, colocalization quantification, EHD1 knockdown endosomal morphology, and a SNX17 KO rat with patch-clamp/optical mapping","pmids":["32041776","30939909"],"confidence":"Medium","gaps":["How EHD1 recruitment is timed relative to cargo capture not resolved","Coat complex linking cargo to fission still undefined"]},{"year":2019,"claim":"Revealed a degradation-control role beyond recycling, in which SNX17 recruits USP9X to deubiquitinate and stabilize PCM1 during ciliogenesis.","evidence":"Co-IP, ubiquitination assays, ciliogenesis readouts under serum starvation","pmids":["31671755"],"confidence":"Medium","gaps":["Whether this is an endosomal recycling function is unclear","Mechanism of USP9X recruitment not structurally defined"]},{"year":2022,"claim":"Mapped the SNX17 C-terminus as a multifunctional interaction module binding both PDLIM PDZ domains and the Commander complex, identifying the structural basis for effector recruitment.","evidence":"Proteomics, PDLIM7-SNX17 co-crystal structure, mutagenesis, biophysical binding assays","pmids":["36302387"],"confidence":"High","gaps":["Functional consequence of PDLIM binding not established","Commander binding region structure with full complex not resolved"]},{"year":2023,"claim":"Placed SNX17 in a defined recycling pathway (SNX17-Retriever-CCC-WASH) required for synaptic plasticity, with PI(3)P- and activity-dependent recruitment driving β1-integrin surface delivery.","evidence":"Knockdown and pathway epistasis in hippocampal neurons, chemical LTP, spine morphology, p140Cap pulldown, and Snx17 haploinsufficient mice","pmids":["37141105","37704928"],"confidence":"Medium","gaps":["Causal order of NMDAR/CaMKII signaling and SNX17 recruitment partly correlative","Full cargo set at synapses incompletely defined"]},{"year":2024,"claim":"Established the autoinhibition logic of the adaptor: cargo binding relieves an intramolecular C-terminal/cargo-pocket contact to expose the Retriever-binding interface, with PI(3)P providing a parallel recruitment input.","evidence":"Recombinant reconstitution with liposomes, structure-guided mutagenesis, biophysical binding quantification","pmids":["39653850"],"confidence":"High","gaps":["In-cell dynamics of the autoinhibition switch not directly observed","How phosphorylation feeds into this switch not yet integrated"]},{"year":2025,"claim":"Defined Ser38 PX-domain phosphorylation as a regulatory switch that abolishes PI(3)P binding and inactivates SNX17 recycling.","evidence":"Phosphomimetic/phosphodead mutagenesis, PI(3)P binding, localization, and cargo recycling assays","pmids":["40349777"],"confidence":"Medium","gaps":["Kinase responsible for Ser38 phosphorylation not identified","Physiological signal triggering this modification unknown"]},{"year":2025,"claim":"Resolved the PCSK9 mechanism on LDLR recycling, showing SNX17 binds an acidic-pH-induced LDLR tail conformation that PCSK9 prevents, diverting LDLR to lysosomes.","evidence":"SNX17 knockdown in cells and Ldlr KO mice, conformational analysis, Co-IP, LDLR recycling assays with mechanistic epistasis","pmids":["40071387"],"confidence":"High","gaps":["Structural basis of pH-dependent tail conformational change not solved","How conformational change couples to FERM/PX engagement unclear"]},{"year":2025,"claim":"Expanded the cargo repertoire and physiological reach of SNX17 sorting to NHE3 stability, dendritic-cell antigen handling, VEGFR degradation, and STAT3-linked metabolism, while preprints define new coat assemblies (WIPI2/CROP2, mutually exclusive Commander assemblies).","evidence":"GST pulldown/mutagenesis (NHE3), DC knockdown functional assays, hindlimb ischemia mouse model (VEGFR), Co-IP (STAT3), and reconstitution/proteomics preprints","pmids":["39559950","40412610","40303303"],"confidence":"Medium","gaps":["STAT3 direct-interaction claim rests on single Co-IP and is Low confidence","VEGFR degradation versus recycling outcome appears cargo-context specific","CROP2/Commander-assembly findings remain preprints awaiting peer review"]},{"year":null,"claim":"How SNX17 integrates the phosphorylation switch, autoinhibition relief, PI(3)P sensing, and selection among distinct Commander/Retriever/WIPI2 coat assemblies to decide individual cargo fate remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of the cargo-loaded, membrane-bound, coat-engaged SNX17 complex","Determinants directing a cargo toward recycling versus degradation undefined","Upstream signaling controlling Ser38 phosphorylation unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,5,16]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,18]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,1,11,18]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,6,19]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,11,16]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,17]}],"complexes":["Retriever (VPS35L/VPS26C)","Commander/CCC complex"],"partners":["VPS35L","VPS26C","EHD1","KRIT1","ITGB1","LRP1","USP9X","OCIAD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15036","full_name":"Sorting nexin-17","aliases":[],"length_aa":470,"mass_kda":52.9,"function":"Critical regulator of endosomal recycling of numerous surface proteins, including integrins, signaling receptor and channels (PubMed:15121882, PubMed:15769472, PubMed:39587083). Binds to NPxY sequences in the cytoplasmic tails of target cargos (PubMed:21512128). Associates with retriever and CCC complexes to prevent lysosomal degradation and promote cell surface recycling of numerous cargos such as integrins ITGB1, ITGB5 and their associated alpha subunits (PubMed:22492727, PubMed:28892079, PubMed:39587083). Also required for maintenance of normal cell surface levels of APP and LRP1 (PubMed:16712798, PubMed:19005208). Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) (PubMed:16712798)","subcellular_location":"Cytoplasm; Early endosome; Cytoplasmic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q15036/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX17","classification":"Not Classified","n_dependent_lines":52,"n_total_lines":1208,"dependency_fraction":0.04304635761589404},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000115234","cell_line_id":"CID000691","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":2},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"NDUFB6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000691","total_profiled":1310},"omim":[{"mim_id":"619839","title":"SORTING NEXIN 31; SNX31","url":"https://www.omim.org/entry/619839"},{"mim_id":"618981","title":"VPS35 ENDOSOMAL PROTEIN-SORTING FACTOR-LIKE; VPS35L","url":"https://www.omim.org/entry/618981"},{"mim_id":"616700","title":"COMM DOMAIN-CONTAINING PROTEIN 3; COMMD3","url":"https://www.omim.org/entry/616700"},{"mim_id":"606932","title":"VPS29 RETROMER COMPLEX COMPONENT; VPS29","url":"https://www.omim.org/entry/606932"},{"mim_id":"605963","title":"SORTING NEXIN 17; SNX17","url":"https://www.omim.org/entry/605963"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Vesicles","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNX17"},"hgnc":{"alias_symbol":["KIAA0064"],"prev_symbol":[]},"alphafold":{"accession":"Q15036","domains":[{"cath_id":"3.30.1520.10","chopping":"2-109","consensus_level":"high","plddt":91.1197,"start":2,"end":109},{"cath_id":"3.10.20.90","chopping":"112-204","consensus_level":"medium","plddt":96.7758,"start":112,"end":204},{"cath_id":"1.20.80.60","chopping":"206-270","consensus_level":"medium","plddt":95.4075,"start":206,"end":270},{"cath_id":"2.30.29.30","chopping":"271-326_345-397","consensus_level":"medium","plddt":90.8174,"start":271,"end":397}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15036","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15036-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15036-F1-predicted_aligned_error_v6.png","plddt_mean":82.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX17","jax_strain_url":"https://www.jax.org/strain/search?query=SNX17"},"sequence":{"accession":"Q15036","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15036.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15036/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15036"}},"corpus_meta":[{"pmid":"22492727","id":"PMC_22492727","title":"SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways.","date":"2012","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22492727","citation_count":175,"is_preprint":false},{"pmid":"12169628","id":"PMC_12169628","title":"The PX-domain protein SNX17 interacts with members of the LDL receptor family and modulates endocytosis of the LDL receptor.","date":"2002","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12169628","citation_count":116,"is_preprint":false},{"pmid":"19005208","id":"PMC_19005208","title":"Polarized traffic of LRP1 involves AP1B and SNX17 operating on Y-dependent sorting motifs in different pathways.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19005208","citation_count":55,"is_preprint":false},{"pmid":"23115288","id":"PMC_23115288","title":"SNX17 facilitates infection with diverse papillomavirus types.","date":"2012","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23115288","citation_count":47,"is_preprint":false},{"pmid":"25825439","id":"PMC_25825439","title":"SNX17 affects T cell activation by regulating TCR and integrin recycling.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25825439","citation_count":41,"is_preprint":false},{"pmid":"40071387","id":"PMC_40071387","title":"PCSK9 Promotes LDLR Degradation by Preventing SNX17-Mediated LDLR Recycling.","date":"2025","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/40071387","citation_count":33,"is_preprint":false},{"pmid":"25059659","id":"PMC_25059659","title":"Structural determinants for binding of sorting nexin 17 (SNX17) to the cytoplasmic adaptor protein Krev interaction trapped 1 (KRIT1).","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25059659","citation_count":29,"is_preprint":false},{"pmid":"32041776","id":"PMC_32041776","title":"Sorting nexin 17 (SNX17) links endosomal sorting to Eps15 homology domain protein 1 (EHD1)-mediated fission machinery.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32041776","citation_count":24,"is_preprint":false},{"pmid":"31671755","id":"PMC_31671755","title":"SNX17 Recruits USP9X to Antagonize MIB1-Mediated Ubiquitination and Degradation of PCM1 during Serum-Starvation-Induced Ciliogenesis.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31671755","citation_count":21,"is_preprint":false},{"pmid":"30939909","id":"PMC_30939909","title":"SNX17 (Sorting Nexin 17) Mediates Atrial Fibrillation Onset Through Endocytic Trafficking of the Kv1.5 (Potassium Voltage-Gated Channel Subfamily A Member 5) Channel.","date":"2019","source":"Circulation. 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family members (LDLR, VLDLR, ApoER2, LRP) via its PX domain, localizes to vesicular structures partially overlapping with EEA1- and Rab4-positive endosomes, and enhances the endocytosis rate of LDLR.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/immunofluorescence colocalization, functional endocytosis assay with rhodamine-labeled LDL\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal binding shown, localization established, functional endocytosis assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12169628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SNX17 recognizes the NPXY motif (N26) in the cytoplasmic tail of LRP1 and mediates its recycling from basolateral sorting endosomes; mutation of this NPXY motif traps LRP1 in the basolateral sorting endosome, establishing SNX17's role in basolateral/somatodendritic recycling.\",\n      \"method\": \"NPXY motif mutagenesis, trafficking assays in polarized MDCK cells and hippocampal neurons, colocalization by immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional trafficking readout, single lab, multiple complementary approaches\",\n      \"pmids\": [\"19005208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SNX17 binds to the membrane-distal NPXY motif in β1 and β5 integrin cytoplasmic tails via its FERM-like domain, thereby preventing lysosomal degradation of β integrins and their associated α subunits; this retrieval does not depend on the retromer complex, and SNX17 depletion impairs cell migration.\",\n      \"method\": \"SILAC-based quantitative proteomics, siRNA knockdown, lysosomal inhibitor assays, co-immunoprecipitation, cell migration assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased proteomic screen plus reciprocal Co-IP, mutagenesis of NPXY motif, lysosomal inhibitor rescue, functional migration readout, replicated across multiple integrin subunits\",\n      \"pmids\": [\"22492727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SNX17 interacts with the HPV-16 L2 capsid protein and is essential for papillomavirus infection; this interaction is conserved across multiple PV types, indicating SNX17 is required for a conserved viral entry mechanism.\",\n      \"method\": \"Infection assays with multiple PV types, SNX17 knockdown, interaction studies with L2 protein\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional knockdown with infection readout across multiple PV types, single lab\",\n      \"pmids\": [\"23115288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SNX17 acts as a cargo-specific adaptor that binds Jag1a and facilitates retromer-dependent recycling of the Notch ligand Jag1 to the plasma membrane in ligand-expressing cells; inhibition disrupts neurogenesis and pancreas development in zebrafish.\",\n      \"method\": \"Co-immunoprecipitation, zebrafish knockdown/rescue experiments, fluorescence localization\",\n      \"journal\": \"Cell regeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — binding plus in vivo genetic epistasis (zebrafish), single lab\",\n      \"pmids\": [\"25408867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SNX17 directly binds KRIT1 through its FERM domain recognizing the second NPXF motif of KRIT1; co-crystal structure at 3.0 Å reveals the interaction is highly similar to the SNX17-P-selectin interaction; site-directed mutagenesis confirms the NPXF2 motif as the major binding site.\",\n      \"method\": \"Co-crystal structure (3.0 Å resolution), site-directed mutagenesis, GST pulldown, binding affinity measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus in vitro pulldown, all in one rigorous study\",\n      \"pmids\": [\"25059659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The FERM domain of SNX17 mediates binding and trafficking of TCR and LFA-1 (integrin) to the cell surface; SNX17 colocalizes with TCR at the immune synapse, and SNX17 knockdown reduces surface TCR and LFA-1 expression, TCR recycling, and T cell–APC conjugate formation.\",\n      \"method\": \"siRNA knockdown, immunofluorescence colocalization, flow cytometry for surface receptor expression, TCR recycling assay, domain truncation analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — domain mapping plus multiple functional readouts, single lab\",\n      \"pmids\": [\"25439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SNX17 FERM domain mediates binding and trafficking of TCR and LFA-1 to the T cell surface, as identified by domain truncation studies.\",\n      \"method\": \"Truncated SNX17 domain expression constructs, immunofluorescence, flow cytometry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — domain truncation with functional trafficking readout, single lab\",\n      \"pmids\": [\"25825439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SNX17 binds SERCA2a protein via its PX (phox-homology) domain, and SNX17 deficiency leads to lysosomal degradation of SERCA2a, intracellular Ca2+ overload, and cardiac arrhythmias; chloroquine (lysosomal inhibitor) prevents SNX17-knockdown-induced SERCA2a reduction.\",\n      \"method\": \"Co-immunoprecipitation with domain mapping, siRNA knockdown, lysosomal inhibitor rescue, Ca2+ imaging, electrocardiography in rat MI model\",\n      \"journal\": \"International journal of cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with domain mapping, lysosomal inhibitor rescue, in vivo model, single lab\",\n      \"pmids\": [\"30025651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNX17 recruits the deubiquitinating enzyme USP9X to antagonize MIB1-mediated ubiquitination and degradation of PCM1 during serum-starvation-induced ciliogenesis; SNX17 deficiency leads to enhanced degradation of both USP9X and PCM1 and disrupts ciliogenesis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ciliogenesis assay, ubiquitination assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP, ubiquitination assay, functional ciliogenesis readout, single lab\",\n      \"pmids\": [\"31671755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNX17 facilitates endocytic sorting of the Kv1.5 potassium channel from the plasma membrane to early endosomes via its FERM domain; SNX17 heterozygous knockout rats show increased membrane Kv1.5 expression, increased IKur, shortened action potential duration, and increased AF susceptibility.\",\n      \"method\": \"SNX17 knockout rat model, patch clamp electrophysiology, optical mapping, immunostaining/confocal, truncated domain expression constructs\",\n      \"journal\": \"Circulation. Arrhythmia and electrophysiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with electrophysiology readout plus domain mapping, single lab\",\n      \"pmids\": [\"30939909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SNX17 directly interacts with EHD1, a dynamin-like fission GTPase; EHD1 is recruited to endosomal membranes upon LRP1 internalization, SNX17 and EHD1 colocalize on endosomes, and EHD1 depletion causes enlargement of SNX17-containing endosomes, indicating EHD1 mediates fission of SNX17-labeled endosomal carriers.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, surface rendering/quantification of colocalization volumes, EHD1 siRNA knockdown with endosomal morphology readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct in vitro interaction plus functional endosomal fission readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"32041776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNX17 interacts with leiomodin-2 (LMOD2) via its C-terminal domain; SNX17 deficiency promotes lysosomal degradation of LMOD2, worsening DOX-induced cardiac systolic dysfunction.\",\n      \"method\": \"Co-immunoprecipitation with domain mapping, siRNA knockdown, lysosomal pathway inhibition, in vivo rat model of cardiotoxicity\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP with domain mapping plus lysosomal inhibitor rescue and in vivo model, single lab\",\n      \"pmids\": [\"33933636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The C-terminus of SNX17 contains a type III PDZ-binding motif that binds PDLIM family proteins; the co-crystal structure of the PDLIM7 PDZ domain with the SNX17 C-terminus reveals an unconventional perpendicular peptide interaction mediated by electrostatic contacts and a conserved proline-containing loop in PDLIM proteins; the C-terminus of SNX17 is also sufficient for Commander complex interaction.\",\n      \"method\": \"Proteomics, co-crystal structure determination, mutagenesis, biophysical binding assays\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus proteomics plus mutagenesis, rigorous multi-method single study\",\n      \"pmids\": [\"36302387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SNX17 pathway (SNX17-Retriever-CCC-WASH) is required in hippocampal neurons for maintenance of excitatory synapses and structural plasticity during chemical LTP; cLTP drives SNX17 recruitment to synapses in a manner requiring NMDAR activation, CaMKII signaling, Retriever binding, and PI(3)P; SNX17 partly mediates LTP effects through regulation of β1-integrin surface expression.\",\n      \"method\": \"siRNA knockdown in cultured hippocampal neurons, chemical LTP induction, immunofluorescence, spine morphology analysis, surface receptor quantification\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown with multiple functional and molecular readouts in neurons, pathway epistasis, single lab\",\n      \"pmids\": [\"37141105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SNX17 interacts with p140Cap (a SRC kinase inhibitor/actin regulator) as identified by GST pulldown and interactome analysis; this interaction is required for dendritic spine maturation, and Snx17 haploinsufficiency in mice impairs synaptic transmission and spine maturation.\",\n      \"method\": \"GST pulldown, interactome/proteomic analysis, Snx17 heterozygous knockout mice, spine morphology, electrophysiology\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct pulldown interaction plus in vivo KO phenotype, single lab\",\n      \"pmids\": [\"37704928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNX17 directly interacts with Retriever through its C-terminal region binding to the VPS35L/VPS26C interface; this interaction is enhanced when SNX17 is bound to cargo (due to disruption of an intramolecular autoinhibitory interaction between the C-terminal region and the cargo-binding pocket); PI(3)P binding by SNX17 also promotes Retriever recruitment independently of cargo.\",\n      \"method\": \"Biophysical assays (binding measurements), structural model-guided mutagenesis, recombinant protein reconstitution with liposomes\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with liposomes, structural modeling, mutagenesis, and biophysical quantification in a single rigorous study\",\n      \"pmids\": [\"39653850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNX17 controls antigen internalisation, integrin recycling, actin cytoskeleton organization, and phagosomal maturation in dendritic cells; SNX17 silencing impairs fluid-phase endocytosis, phagocytosis, and T. gondii invasion, and disrupts cross-presentation.\",\n      \"method\": \"siRNA knockdown in dendritic cells, functional endocytosis/phagocytosis assays, integrin recycling assays, actin staining, cross-presentation assay\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — knockdown with multiple functional readouts, single lab\",\n      \"pmids\": [\"39559950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Phosphorylation of SNX17 at serine 38 (Ser38) within the PX domain disrupts SNX17 binding to PI(3)P, impairs its association with early endosomal membranes, inactivates SNX17-dependent cargo recycling, and is part of an autoinhibitory mechanism regulating cargo binding.\",\n      \"method\": \"Phosphomimetic/phosphodead mutagenesis, PI(3)P binding assays, endosomal localization assays, cargo recycling assays in cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with multiple functional readouts (lipid binding, localization, cargo recycling), single lab\",\n      \"pmids\": [\"40349777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Acidic pH induces a conformational change in the LDLR extracellular domain that promotes interaction between LDLR intracellular domain and SNX17; PCSK9 prevents this acidic pH-induced conformational change, thereby blocking SNX17-LDLR interaction and diverting LDLR to lysosomal degradation; SNX17 knockdown abolishes LDLR recycling and PCSK9-mediated LDLR degradation.\",\n      \"method\": \"SNX17 knockdown in cells and Ldlr KO mice, in vitro and in vivo approaches, conformational change analysis, co-immunoprecipitation, LDLR recycling assays\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo KO models, multiple orthogonal methods, mechanistic epistasis (SNX17 KD abolishes PCSK9 effect), replicated across cell and animal systems\",\n      \"pmids\": [\"40071387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX17 directly interacts with STAT3 and promotes STAT3 phosphorylation in a retromer-dependent manner; the SNX17-retromer complex acts as a platform for IL-6-induced STAT3 activation, leading to c-Myc upregulation and enhanced mitochondrial OXPHOS.\",\n      \"method\": \"Co-immunoprecipitation, STAT3 inhibitor treatment, STAT3 knockdown, retromer knockdown, OXPHOS measurement\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for direct interaction claim, limited mechanistic validation of direct versus indirect STAT3 activation, single lab\",\n      \"pmids\": [\"40303303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX17 interacts with the C-terminus of NHE3 (Na+/H+ exchanger 3) via an NPxY motif; mutation of the distal NPxY motif in NHE3 disrupts this interaction, leading to reduced NHE3 expression and increased degradation; SNX17 knockdown reduces NHE3 activity and stability.\",\n      \"method\": \"GST pulldown with NPxY motif mutagenesis, siRNA knockdown, NHE3 activity assay, degradation assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct pulldown with mutagenesis confirming binding site plus functional stability readout, single lab, preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WIPI2 (a PROPPIN) integrates into Retriever-dependent coat complexes by interacting with both the Commander subunit CCDC93 and SNX17, forming the CROP2 complex; CROP2 is required for endosomal recycling of β1-integrin but not for CROP (Retromer)-dependent cargos.\",\n      \"method\": \"Co-immunoprecipitation, functional recycling assays, genetic depletion of WIPI2\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — binding interaction plus pathway-selective cargo recycling assay, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX17-Commander and RAB32-LRMDA-Commander assemblies are mutually exclusive; LRMDA and SNX17 share a common mechanism of Commander association; SNX17-Commander mediates cell surface recycling while RAB32-LRMDA-Commander mediates melanosome biogenesis in melanocytes.\",\n      \"method\": \"Unbiased proteomics, recombinant protein reconstitution, computational modelling, functional assays in human melanocytes\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — recombinant reconstitution plus proteomics plus functional cellular assays, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PI(3)P synthesis during chemical LTP drives coordinate recruitment of both the SNX17-Retriever and SNX27-Retromer pathways to endosomes and synaptic sites; preventing PI(3)P synthesis blocks SNX17 synaptic recruitment, decreases cargo recycling, and blocks LTP in cultured neurons and hippocampal slices.\",\n      \"method\": \"PI(3)P synthesis inhibition, live imaging, chemical LTP in hippocampal neurons and slices, cargo recycling assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus functional LTP readout in neurons and slices, single lab\",\n      \"pmids\": [\"40920104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX17 promotes lysosomal degradation of VEGFR; in the absence of SNX17, VEGFR accumulates in early endosomes with prolonged activation, promoting angiogenesis; SNX17 knockdown in hindlimb ischemia mice increases blood flow and limb salvage.\",\n      \"method\": \"SNX17 knockdown in cells and hindlimb ischemia mouse model, endosomal localization assays, angiogenesis assays\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vivo KO with functional angiogenesis readout plus mechanistic endosomal localization data, single lab\",\n      \"pmids\": [\"40412610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"OCIAD2 binds SNX17 and enhances its association with integrin β1, promoting integrin β1 recycling to lipid raft-enriched plasma membrane regions and preventing its lysosomal degradation; this sustains FAK-PI3K-AKT-mTOR signaling.\",\n      \"method\": \"Co-immunoprecipitation with mass spectrometry, siRNA knockdown, recycling and degradation assays, lipid raft fractionation\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP/MS plus functional recycling/degradation assays, single lab\",\n      \"pmids\": [\"41655222\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNX17 is a FERM-domain- and PX-domain-containing endosomal sorting adaptor that localizes to early/sorting endosomes via PI(3)P binding through its PX domain (regulated by Ser38 phosphorylation), directly recognizes NPX(Y/F) motifs in cytoplasmic tails of transmembrane cargo proteins (integrins, LDL receptor family members, Kv1.5, NHE3, KRIT1, and others) through its FERM domain, recruits the Retriever complex (via its C-terminal region binding VPS35L/VPS26C) and the EHD1 fission machinery to mediate endosomal recycling of cargo to the plasma membrane, operates together with the Commander/CCC/WASH complex, and thereby prevents lysosomal degradation of its cargos; its activity is autoinhibited by an intramolecular C-terminal/cargo-pocket interaction that is relieved upon cargo and PI(3)P binding, and the pathway is required for integrin-dependent cell migration, T cell activation, synaptic plasticity, and LDLR recycling (the latter being blocked by PCSK9).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNX17 is an endosomal sorting adaptor that recognizes NPX(Y/F) motifs in the cytoplasmic tails of transmembrane cargo and retrieves them from the degradative pathway for recycling back to the plasma membrane [#2, #5]. It engages a broad cargo set through distinct domains: its FERM-like domain binds the membrane-distal NPXY/NPXF motifs of \\u03b21/\\u03b25 integrins, KRIT1, and NHE3 [#2, #5, #21], while its PX domain mediates association with LDL receptor family members and anchors SNX17 to PI(3)P-positive early/sorting endosomes [#0, #18]. Cargo capture protects substrates from lysosomal degradation, as shown for integrins [#2], SERCA2a [#8], and LDLR [#19], and is the basis for SNX17's role in integrin-dependent cell migration [#2]. SNX17 executes recycling by recruiting the Retriever complex through its C-terminal region binding the VPS35L/VPS26C interface, operating together with the Commander/CCC and WASH machinery, and by recruiting the EHD1 fission GTPase to bud SNX17-coated carriers [#11, #13, #16]. Its activity is autoinhibited by an intramolecular contact between the C-terminal region and the cargo-binding pocket that is relieved upon cargo and PI(3)P binding, and cargo recycling is further gated by Ser38 phosphorylation in the PX domain that abolishes PI(3)P binding [#16, #18]. Through this sorting function SNX17 supports T cell receptor and LFA-1 surface delivery and immune synapse formation [#6], antigen processing and cross-presentation in dendritic cells [#17], and synaptic structural plasticity during LTP via \\u03b21-integrin recycling [#14, #24]. In lipoprotein metabolism, SNX17 binds an acidic-pH-induced conformation of the LDLR tail to recycle the receptor, a step that PCSK9 blocks to divert LDLR to lysosomal degradation [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established SNX17 as a direct binder of LDL receptor family cytoplasmic domains and an endosomal protein influencing receptor endocytosis, opening the question of how it sorts membrane cargo.\",\n      \"evidence\": \"Co-IP, fractionation/colocalization with EEA1 and Rab4, and LDL endocytosis assays\",\n      \"pmids\": [\"12169628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding ascribed to PX domain rather than later-defined FERM cargo pocket\", \"No recycling machinery identified\", \"Single cargo family tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the NPXY motif as the cargo recognition signal and placed SNX17 in basolateral/somatodendritic recycling of LRP1.\",\n      \"evidence\": \"NPXY mutagenesis with trafficking readouts in polarized MDCK cells and neurons\",\n      \"pmids\": [\"19005208\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain responsible for NPXY recognition not yet mapped\", \"Downstream coat/fission machinery unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed SNX17 retrieves \\u03b2 integrins from lysosomal degradation via FERM-domain NPXY recognition independent of retromer, linking the adaptor to cell migration and broadening its cargo repertoire to integrins and viral entry.\",\n      \"evidence\": \"SILAC proteomics, NPXY mutagenesis, lysosomal inhibitor rescue, migration assays, and PV infection knockdown studies\",\n      \"pmids\": [\"22492727\", \"23115288\", \"25408867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the recycling effector complex not yet defined\", \"Retromer-independence left open which machinery substitutes\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided atomic-resolution definition of FERM-domain NPXF cargo recognition through the SNX17-KRIT1 co-crystal structure.\",\n      \"evidence\": \"3.0 \\u00c5 co-crystal structure, GST pulldown, site-directed mutagenesis, affinity measurements\",\n      \"pmids\": [\"25059659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure captures cargo binding but not autoinhibited or membrane-bound states\", \"No coat complex in the structure\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended SNX17 cargo handling to immune receptors, showing FERM-dependent surface delivery of TCR and LFA-1 underlies T cell activation.\",\n      \"evidence\": \"Domain truncation, siRNA knockdown, flow cytometry surface quantification, TCR recycling and conjugate assays\",\n      \"pmids\": [\"25825439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recycling effector machinery not defined in T cells\", \"Direct vs indirect TCR binding not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that SNX17 loss drives lysosomal degradation of SERCA2a, with physiological consequences for cardiac Ca2+ handling and arrhythmia.\",\n      \"evidence\": \"Co-IP domain mapping, lysosomal inhibitor rescue, Ca2+ imaging, ECG in a rat MI model\",\n      \"pmids\": [\"30025651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PX-domain-mediated binding to an intracellular cargo differs from NPXY paradigm\", \"Recycling versus stabilization mechanism unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified EHD1 as the fission GTPase that resolves SNX17 carriers and showed SNX17 sorts Kv1.5, connecting the adaptor to endosomal membrane budding and ion channel surface levels.\",\n      \"evidence\": \"In vitro EHD1 binding, colocalization quantification, EHD1 knockdown endosomal morphology, and a SNX17 KO rat with patch-clamp/optical mapping\",\n      \"pmids\": [\"32041776\", \"30939909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How EHD1 recruitment is timed relative to cargo capture not resolved\", \"Coat complex linking cargo to fission still undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a degradation-control role beyond recycling, in which SNX17 recruits USP9X to deubiquitinate and stabilize PCM1 during ciliogenesis.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, ciliogenesis readouts under serum starvation\",\n      \"pmids\": [\"31671755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this is an endosomal recycling function is unclear\", \"Mechanism of USP9X recruitment not structurally defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped the SNX17 C-terminus as a multifunctional interaction module binding both PDLIM PDZ domains and the Commander complex, identifying the structural basis for effector recruitment.\",\n      \"evidence\": \"Proteomics, PDLIM7-SNX17 co-crystal structure, mutagenesis, biophysical binding assays\",\n      \"pmids\": [\"36302387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of PDLIM binding not established\", \"Commander binding region structure with full complex not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed SNX17 in a defined recycling pathway (SNX17-Retriever-CCC-WASH) required for synaptic plasticity, with PI(3)P- and activity-dependent recruitment driving \\u03b21-integrin surface delivery.\",\n      \"evidence\": \"Knockdown and pathway epistasis in hippocampal neurons, chemical LTP, spine morphology, p140Cap pulldown, and Snx17 haploinsufficient mice\",\n      \"pmids\": [\"37141105\", \"37704928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal order of NMDAR/CaMKII signaling and SNX17 recruitment partly correlative\", \"Full cargo set at synapses incompletely defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the autoinhibition logic of the adaptor: cargo binding relieves an intramolecular C-terminal/cargo-pocket contact to expose the Retriever-binding interface, with PI(3)P providing a parallel recruitment input.\",\n      \"evidence\": \"Recombinant reconstitution with liposomes, structure-guided mutagenesis, biophysical binding quantification\",\n      \"pmids\": [\"39653850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell dynamics of the autoinhibition switch not directly observed\", \"How phosphorylation feeds into this switch not yet integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined Ser38 PX-domain phosphorylation as a regulatory switch that abolishes PI(3)P binding and inactivates SNX17 recycling.\",\n      \"evidence\": \"Phosphomimetic/phosphodead mutagenesis, PI(3)P binding, localization, and cargo recycling assays\",\n      \"pmids\": [\"40349777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for Ser38 phosphorylation not identified\", \"Physiological signal triggering this modification unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the PCSK9 mechanism on LDLR recycling, showing SNX17 binds an acidic-pH-induced LDLR tail conformation that PCSK9 prevents, diverting LDLR to lysosomes.\",\n      \"evidence\": \"SNX17 knockdown in cells and Ldlr KO mice, conformational analysis, Co-IP, LDLR recycling assays with mechanistic epistasis\",\n      \"pmids\": [\"40071387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of pH-dependent tail conformational change not solved\", \"How conformational change couples to FERM/PX engagement unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the cargo repertoire and physiological reach of SNX17 sorting to NHE3 stability, dendritic-cell antigen handling, VEGFR degradation, and STAT3-linked metabolism, while preprints define new coat assemblies (WIPI2/CROP2, mutually exclusive Commander assemblies).\",\n      \"evidence\": \"GST pulldown/mutagenesis (NHE3), DC knockdown functional assays, hindlimb ischemia mouse model (VEGFR), Co-IP (STAT3), and reconstitution/proteomics preprints\",\n      \"pmids\": [\"39559950\", \"40412610\", \"40303303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"STAT3 direct-interaction claim rests on single Co-IP and is Low confidence\", \"VEGFR degradation versus recycling outcome appears cargo-context specific\", \"CROP2/Commander-assembly findings remain preprints awaiting peer review\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SNX17 integrates the phosphorylation switch, autoinhibition relief, PI(3)P sensing, and selection among distinct Commander/Retriever/WIPI2 coat assemblies to decide individual cargo fate remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of the cargo-loaded, membrane-bound, coat-engaged SNX17 complex\", \"Determinants directing a cargo toward recycling versus degradation undefined\", \"Upstream signaling controlling Ser38 phosphorylation unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 5, 16]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 18]},\n      {\"term_id\": \"GO:0005515\", \"supporting_discovery_ids\": [2, 5, 11, 13, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 1, 11, 18]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 6, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 11, 16]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 17]}\n    ],\n    \"complexes\": [\n      \"Retriever (VPS35L/VPS26C)\",\n      \"Commander/CCC complex\"\n    ],\n    \"partners\": [\n      \"VPS35L\",\n      \"VPS26C\",\n      \"EHD1\",\n      \"KRIT1\",\n      \"ITGB1\",\n      \"LRP1\",\n      \"USP9X\",\n      \"OCIAD2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"SNX17","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"medium","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 25439"},"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}