{"gene":"SNX5","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2006,"finding":"SNX5 and SNX6 are required for retromer-mediated endosome-to-trans-Golgi-network retrieval of the cation-independent mannose-6-phosphate receptor (CI-MPR); RNAi knockdown of SNX5 or SNX6 induced a phenotype similar to suppression of known retromer components. SNX5 co-localizes with SNX1 on early endosomes, but unlike SNX6, SNX5 did not appear to form a complex with SNX1 by immunoprecipitation. Suppression of SNX5 and/or SNX6 resulted in significant post-translational loss of SNX1.","method":"RNAi loss-of-function screen, immunoprecipitation, co-localization imaging","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic RNAi screen with defined functional readout (CI-MPR trafficking), co-localization and immunoprecipitation, multiple retromer components tested as controls","pmids":["17148574"],"is_preprint":false},{"year":1999,"finding":"SNX5 binds to the Fanconi anemia complementation group A (FANCA) protein; the interaction was identified by yeast two-hybrid and confirmed by immunoprecipitation. The PX domain of SNX5 is not required for this binding. Overexpression of SNX5 increased FANCA protein levels.","method":"Yeast two-hybrid screen, immunoprecipitation, deletion mutant analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP and deletion mapping, single lab","pmids":["10600472"],"is_preprint":false},{"year":2008,"finding":"SNX5 promotes macropinocytosis; it is recruited to newly-formed macropinosomes and to EGF receptor-positive plasma membrane regions. Stable overexpression of GFP-SNX5 in HEK cells approximately doubled constitutive and EGF-stimulated macropinosome formation. SNX5 PX domain binds specifically PtdIns(3)P and PtdIns(3,4)P2, and inhibition of EGF receptor tyrosine kinase (AG1478) prevented SNX5 recruitment to the plasma membrane.","method":"Live-cell imaging, stable GFP-SNX5 expression, phosphoinositide-binding assays, EGF receptor inhibitor treatment, macropinosome quantification","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined functional phenotype with multiple orthogonal approaches, single lab","pmids":["18854019"],"is_preprint":false},{"year":2012,"finding":"SNX5 is essential for macropinosome biogenesis in primary macrophages and for antigen uptake/processing. Depletion of SNX5 in bone marrow-derived macrophages dramatically reduced macropinosome number and size and reduced uptake and processing of soluble ovalbumin. SNX1 knockout had no effect on SNX5 localization or macropinosome biogenesis, demonstrating SNX5 can function independently of SNX1.","method":"siRNA knockdown in primary macrophages, SNX1 knockout mice, fluorescence microscopy, ovalbumin uptake assay","journal":"Biology open","confidence":"High","confidence_rationale":"Tier 2 / Strong — primary cell knockdown and knockout model with defined functional readouts, replicated in two genetic settings","pmids":["23213485"],"is_preprint":false},{"year":2008,"finding":"The DHR1 domain of DOCK180 interacts with SNX5 (and SNX1, 2, 6); SNX5 was the most efficiently co-immunoprecipitated among these. DOCK180 co-localizes with SNX5 at endosomes. RNAi knockdown of SNX5 or DOCK180 (but not Rac1) caused redistribution of CI-MPR from TGN to endosomes. Expression of the DHR1 domain alone was sufficient to restore CI-MPR distribution in DOCK180 knockdown cells, indicating DOCK180 regulates CI-MPR trafficking via SNX5 independently of its GEF activity.","method":"LC-MS/MS pulldown, co-immunoprecipitation, co-localization imaging, RNAi knockdown, CI-MPR trafficking assay, domain rescue experiment","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, mass spectrometry identification, domain rescue, multiple functional readouts in one study","pmids":["18596235"],"is_preprint":false},{"year":2006,"finding":"Zebrafish Snx5 is a binding partner of the E3 ubiquitin ligase Mind bomb (Mib); Snx5 co-localizes with Mind bomb in early endosomal compartments. Morpholino knockdown of snx5 caused defects in hematopoiesis and blood vessel development in zebrafish embryos.","method":"Yeast two-hybrid, co-localization imaging, morpholino knockdown in zebrafish","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid interaction confirmed by co-localization with in vivo loss-of-function phenotype, single lab","pmids":["16857196"],"is_preprint":false},{"year":2015,"finding":"In zebrafish retinal development, SNX5 co-localizes with Mind bomb and Delta complexes and directly binds Mib. SNX5 functions downstream of miR-216a to regulate Notch signaling: knockdown of snx5 decreased Notch activation, whereas overexpression of snx5 increased it, placing SNX5 as a positive component of the Notch pathway through promoting endocytosis of Delta.","method":"co-localization, direct binding (co-IP), morpholino knockdown, snx5 overexpression, Notch signaling reporters in zebrafish","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (gain- and loss-of-function with defined Notch pathway readout), single lab","pmids":["25645681"],"is_preprint":false},{"year":2017,"finding":"Renal SNX5 co-localizes and co-immunoprecipitates with insulin-degrading enzyme (IDE) at the plasma membrane and perinuclear area of human renal proximal tubule cells; insulin stimulation increases their co-localization and co-immunoprecipitation. Silencing SNX5 in cultured cells and in mouse kidney decreased IDE expression and activity, leading to insulin resistance and elevated blood glucose and insulin in vivo.","method":"Co-immunoprecipitation, co-localization, siRNA silencing in cells, renal-selective siRNA delivery via osmotic mini-pump in mice, IDE activity assay, metabolic phenotyping","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (co-IP, co-localization, in vitro silencing, in vivo silencing with functional metabolic readout), replicated in rat and mouse models","pmids":["29080975"],"is_preprint":false},{"year":2019,"finding":"SNX5 negatively regulates RLR-mediated antiviral signaling: overexpression of SNX5 inhibited virus-induced IFN-β promoter, ISRE, NF-κB, and IRF3 activation, while SNX5 knockdown had the opposite effect. SNX5 overexpression promoted K48-linked (degradative) ubiquitination and reduced K63-linked ubiquitination of RIG-I, reducing RIG-I protein levels. SNX5 overexpression also weakened the VISA-TRAF2/5 interaction.","method":"Overexpression and RNAi knockdown, luciferase reporter assays for IFN-β/ISRE/NF-κB/IRF3, ubiquitination assay (K48 vs K63), co-immunoprecipitation of VISA-TRAF2/5","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple reporter and biochemical assays in single lab, no structural or in vitro reconstitution","pmids":["31806368"],"is_preprint":false},{"year":2022,"finding":"SNX5 mediates retrograde transport of the vesicular monoamine transporter (VMAT) from endosomes to the TGN, which is required for AP-3-dependent assembly of VMAT into dense core vesicles (DCVs). Loss of SNX5 disrupts VMAT trafficking to DCVs and impairs regulated monoamine release.","method":"SNX5 loss-of-function, VMAT trafficking assay, DCV monoamine release assay, genetic interaction with AP-3","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined cargo (VMAT) and organelle (TGN/DCV) with loss-of-function phenotype, functional monoamine release assay, genetic epistasis with AP-3","pmids":["35426896"],"is_preprint":false},{"year":2023,"finding":"SNX5 interacts with VPS13A via the VPS13 adaptor-binding (VAB) domain of VPS13A and a PxP motif in SNX5 (analogous to yeast Ypt35-Vps13 interaction). This interaction mediates VPS13A association with endosomal subdomains. A pathogenic asparagine mutation in the VAB domain impairs this interaction.","method":"Co-immunoprecipitation/pulldown, co-localization, domain mapping, mutant analysis","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction mapping with domain and pathogenic mutation validation, single lab","pmids":["36977596"],"is_preprint":false},{"year":2024,"finding":"CHC22 clathrin C-terminal trimerization domain interacts with SNX5 (and functionally redundant SNX6), and this interaction is required for CHC22 recruitment to ERGIC membranes. SNX5 also binds the ERGIC tether p115. Both the CHC22-SNX5 and CHC22-p115 interactions are required for CHC22-mediated Golgi-bypass trafficking of GLUT4 to the intracellular GLUT4 storage compartment; disruption of either interaction inhibits GLUT4 targeting.","method":"Co-immunoprecipitation, domain mapping, GLUT4 trafficking assay, CHC22/SNX5/SNX6 knockdown/knockout, localization imaging","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with domain mapping, loss-of-function studies for both interaction partners, defined cargo (GLUT4) and organelle trafficking readout","pmids":["39160272"],"is_preprint":false},{"year":2024,"finding":"SNX5 directly binds Rab11a in cardiomyocytes, increasing Rab11a membrane accumulation. This SNX5-Rab11a interaction promotes membrane translocation of LRP6, a regulator of cardiac hypertrophy. siRNA silencing of Rab11a abolished the LRP6 membrane accumulation induced by SNX5 overexpression.","method":"Co-immunoprecipitation, fluorescence co-localization, membrane protein fractionation, siRNA knockdown, AAV9-mediated cardiac-specific overexpression in TAC mouse model, echocardiography","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, co-localization, and epistasis (siRab11a) with in vivo cardiac model; single lab","pmids":["38950816"],"is_preprint":false},{"year":2024,"finding":"SNX5 regulates actin-dependent plasma membrane remodeling in B cells and endolysosomal trafficking at the immune synapse. SNX5-depleted B cells showed enlarged lysosomes not recruited to the synaptic membrane, reducing antigen extraction and presentation capacity.","method":"siRNA silencing, live-cell imaging, lysosome morphology analysis, antigen extraction assay at immune synapse","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (lysosome recruitment, antigen presentation), multiple imaging-based readouts, single lab","pmids":["39448266"],"is_preprint":false},{"year":2025,"finding":"SNX5 is a substrate of the E3 ubiquitin ligase MuRF2, which ubiquitinates SNX5 at lysines 290 and 324, leading to its proteasomal degradation. MuRF3 counteracts this effect. SNX5 stabilizes PKA regulatory subunit RI-α within early endosomes; SNX5 knockout reduced RI-α stability, enhanced PKA activity, increased HDAC5 degradation, and upregulated myostatin via MEF2, impairing myogenic differentiation. Both coiled-coil domains of MuRF3 and the BAR domain of SNX5 mediate the MuRF2/3-SNX5 interaction.","method":"SILAC/AP-MS, co-immunoprecipitation, domain mapping, ubiquitination assay with K290/324 site identification, CRISPR-KO, siRNA, endosome isolation, mass spectrometry of endosomal cargo, myogenic differentiation assays","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"High","confidence_rationale":"Tier 1 / Strong — ubiquitination assay with specific lysine identification, mass spectrometry cargo identification, CRISPR-KO with multiple functional readouts, domain mapping, multiple orthogonal methods in one study","pmids":["41077709"],"is_preprint":false},{"year":2025,"finding":"SNX5 knockdown protects neurons from alpha-synuclein-induced toxicity. Extracellular or overexpressed intracellular alpha-synuclein caused fragmentation of the trans-Golgi network, which was prevented by SNX5 knockdown; SNX5 knockdown confined alpha-synuclein to early endosomes. This was confirmed in primary neurons from transgenic mice.","method":"Genome-wide siRNA screen, independent siRNA validation, immunofluorescence microscopy, primary neuron culture from transgenic mice, qPCR, Western blot","journal":"Translational neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated genome-wide screen hit confirmed in primary neurons with defined mechanistic readout (TGN fragmentation, alpha-synuclein compartmentalization), single lab","pmids":["40457499"],"is_preprint":false},{"year":2025,"finding":"SNX5 interacts directly with NCOA7-AS (the short antiviral isoform of NCOA7). Crystal structures of NCOA7-AS/SNX5 complexes revealed that the SNX5-interaction motif in NCOA7-AS resembles known cargo motifs recognized by SNX5/6. Specific critical residues at the interface were identified as important for binding and antiviral activity against influenza A virus. SNX5 (and SNX6) are essential for NCOA7-AS antiviral activity.","method":"Mass spectrometry pulldown (NCOA7-AS partners), co-IP, crystal structure determination, site-directed mutagenesis, antiviral activity assays","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutagenesis and functional validation (antiviral assay), single lab preprint","pmids":[],"is_preprint":true},{"year":2025,"finding":"Molecular dynamics and metadynamics simulations of SNX1-SNX5 heterodimer on membranes show that SNX5-PXD interacts with the CI-MPR cargo tail via aromatic (π-π) interactions, with a favorable binding free energy. SNX1-PXD provides robust membrane binding largely insensitive to mutation of basic residues. These computational models, benchmarked against available cryo-EM structures of SNX1 homodimer and SNX1-SNX5 heterodimer, support a division of labor: SNX1 handles membrane curvature/binding and SNX5 handles cargo recognition.","method":"All-atom molecular dynamics, metadynamics simulations, continuum mechanics (DTS) mesoscopic simulation, benchmarking against cryo-EM structures","journal":"Biophysical journal","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational predictions only, no direct experimental validation of binding in this paper","pmids":["41206513"],"is_preprint":false},{"year":2025,"finding":"SNX5 facilitates recycling of phosphorylated EGFR (p-EGFR) back to the plasma membrane to sustain EGFR signaling; loss of SNX5 redirects EGFR trafficking toward late endosomes and lysosomal degradation, thereby attenuating EGFR signaling and mechanosensitive osteogenic differentiation.","method":"Multi-dataset screening, functional loss-of-function studies, EGFR trafficking assay, in vivo SNX5-deficient model with implant placement","journal":"International journal of oral science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cargo (EGFR) and trafficking readout plus in vivo model, single lab","pmids":["41714616"],"is_preprint":false},{"year":2025,"finding":"USP46 deubiquitinates SNX5, increasing its stability. SNX5 knockdown abolished the ferroptosis-promoting effect of USP46 in ischemia-reperfusion-treated neuronal cells, placing SNX5 downstream of USP46 in a ferroptosis-promoting pathway.","method":"Mass spectrometry (USP46 interactors), co-immunoprecipitation, deubiquitination assay, SNX5 siRNA knockdown, ferroptosis assays, in vivo rat I/R model","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and deubiquitination assay with epistasis (SNX5 KD rescues USP46 OE phenotype), single lab","pmids":["39909216"],"is_preprint":false},{"year":2025,"finding":"SNX5 interacts with LRP5 in gastric cancer cells; SNX5 inhibits LRP5 internalization and promotes its recycling to the cell membrane, preventing lysosomal degradation of LRP5. Increased membrane LRP5 facilitates β-catenin stabilization and Wnt pathway activation.","method":"Co-immunoprecipitation, LRP5 internalization/recycling assay, β-catenin stabilization assay, SNX5 knockdown/overexpression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction shown by co-IP, receptor trafficking assay with functional pathway readout, single lab","pmids":["39922976"],"is_preprint":false}],"current_model":"SNX5 is a BAR-PX domain sorting nexin that functions on early endosomes and the TGN as a multifunctional trafficking regulator: it forms heterodimers (primarily with SNX1 or SNX6 as part of the retromer/ESCPE-1 machinery) to mediate retrograde endosome-to-TGN retrieval of cargo including CI-MPR and VMAT; its PX domain binds PtdIns(3)P and PtdIns(3,4)P2 to direct membrane recruitment; it promotes macropinocytosis, antigen presentation in macrophages and B cells, and Notch pathway activation (via Mind bomb endocytosis); it interacts with and stabilizes IDE (regulating insulin metabolism), with VPS13A (mediating endosomal lipid transfer), with Rab11a (promoting LRP6/LRP5 membrane recycling), with FANCA, and with DOCK180 (linking GEF-independent CI-MPR trafficking); it is ubiquitinated by MuRF2 at K290/K324 for proteasomal degradation (counteracted by MuRF3), and is deubiquitinated/stabilized by USP46; it is required for CHC22-mediated Golgi-bypass GLUT4 trafficking via interaction with both CHC22 and p115 at the ERGIC; and it negatively regulates innate antiviral signaling by promoting degradative K48-ubiquitination of RIG-I and disrupting the VISA-TRAF2/5 interaction."},"narrative":{"mechanistic_narrative":"SNX5 is a BAR-PX domain sorting nexin that governs endosomal cargo sorting and membrane remodeling, functioning both within retromer/retrograde machinery and in independent trafficking routes [PMID:17148574, PMID:18596235]. Its PX domain binds PtdIns(3)P and PtdIns(3,4)P2 to direct membrane recruitment, and it promotes macropinosome biogenesis at EGF receptor-positive plasma membrane regions [PMID:18854019]. In retrograde transport, SNX5 (cooperating with SNX6) is required for endosome-to-TGN retrieval of CI-MPR and of the vesicular monoamine transporter, the latter feeding AP-3-dependent dense core vesicle assembly and regulated monoamine release [PMID:17148574, PMID:35426896]; within the SNX1-SNX5 dimer, SNX5 contributes cargo recognition through its PX domain [PMID:41206513]. SNX5 directs cargo recycling to the plasma membrane, sustaining EGFR signaling by diverting receptors from lysosomal degradation [PMID:41714616] and, via interaction with Rab11a and LRP6/LRP5, promoting receptor membrane accumulation and Wnt/β-catenin activation [PMID:38950816, PMID:39922976]. It is essential for macropinocytosis and antigen uptake/processing in macrophages, and for endolysosomal trafficking and membrane remodeling at the B-cell immune synapse [PMID:23213485, PMID:39448266]. SNX5 additionally serves as a protein-interaction hub: it stabilizes insulin-degrading enzyme to control insulin metabolism in renal cells [PMID:29080975], binds the E3 ligase Mind bomb to drive Delta endocytosis and Notch activation [PMID:16857196, PMID:25645681], associates with VPS13A to recruit it to endosomal subdomains [PMID:36977596], and partners with CHC22 clathrin and the tether p115 at the ERGIC to enable Golgi-bypass GLUT4 trafficking [PMID:39160272]. SNX5 negatively regulates RIG-I-mediated antiviral signaling by promoting K48-linked degradative ubiquitination of RIG-I and weakening the VISA-TRAF2/5 interaction [PMID:31806368]. SNX5 abundance is set by ubiquitin turnover: MuRF2 ubiquitinates it at K290/K324 for proteasomal degradation (counteracted by MuRF3), while USP46 deubiquitinates and stabilizes it; through endosomal stabilization of the PKA regulatory subunit RI-α, SNX5 modulates myogenic differentiation [PMID:41077709, PMID:39909216].","teleology":[{"year":1999,"claim":"Established the first SNX5 binding partner, linking it to the Fanconi anemia protein FANCA and to protein stabilization, before its endosomal role was defined.","evidence":"Yeast two-hybrid screen with co-IP and deletion mapping in human cells","pmids":["10600472"],"confidence":"Medium","gaps":["PX domain dispensable for binding but functional consequence of the interaction unresolved","single lab, no in vivo validation","no connection drawn to later-defined trafficking roles"]},{"year":2006,"claim":"Placed SNX5 in the retromer pathway by showing it is required for endosome-to-TGN retrieval of CI-MPR, defining its core trafficking function.","evidence":"RNAi loss-of-function screen with CI-MPR trafficking readout, co-localization and IP in mammalian cells","pmids":["17148574"],"confidence":"High","gaps":["SNX5 did not co-IP with SNX1 unlike SNX6, leaving dimerization partner ambiguous","mechanism of SNX1 stabilization by SNX5/SNX6 not resolved"]},{"year":2006,"claim":"Connected SNX5 to developmental signaling by identifying Mind bomb as a partner and showing loss-of-function disrupts hematopoiesis and vasculogenesis in vivo.","evidence":"Yeast two-hybrid, co-localization and morpholino knockdown in zebrafish","pmids":["16857196"],"confidence":"Medium","gaps":["mechanistic link between Mind bomb binding and developmental phenotype not yet defined","single model organism"]},{"year":2008,"claim":"Defined the membrane-recruitment logic of SNX5, showing its PX domain selects PtdIns(3)P/PtdIns(3,4)P2 and that it actively drives macropinosome formation downstream of EGFR.","evidence":"Live-cell imaging, phosphoinositide-binding assays and EGFR inhibitor treatment with macropinosome quantification","pmids":["18854019"],"confidence":"Medium","gaps":["how EGFR activity drives SNX5 plasma membrane recruitment mechanistically unresolved","performed in overexpression HEK system"]},{"year":2008,"claim":"Revealed a GEF-independent role for DOCK180 in CI-MPR trafficking acting through SNX5, expanding the partner network controlling retrograde sorting.","evidence":"LC-MS/MS pulldown, reciprocal co-IP, RNAi and DHR1 domain rescue of CI-MPR distribution","pmids":["18596235"],"confidence":"High","gaps":["how DOCK180-SNX5 binding controls cargo selection mechanistically unclear","Rac1-independence shown but downstream effectors undefined"]},{"year":2012,"claim":"Demonstrated SNX5 is essential for macropinocytosis and antigen processing in primary macrophages and can act independently of SNX1, distinguishing its function from its dimer partner.","evidence":"siRNA knockdown in primary macrophages, SNX1-knockout mice, ovalbumin uptake/processing assays","pmids":["23213485"],"confidence":"High","gaps":["partner(s) supporting SNX1-independent function not identified","molecular basis of macropinosome size/number control unresolved"]},{"year":2015,"claim":"Positioned SNX5 as a positive Notch pathway component acting downstream of miR-216a by promoting Delta endocytosis via Mind bomb.","evidence":"Co-localization, co-IP, morpholino loss- and gain-of-function with Notch reporters in zebrafish retina","pmids":["25645681"],"confidence":"Medium","gaps":["how SNX5-Mib binding mechanically drives Delta internalization not shown","single developmental context"]},{"year":2017,"claim":"Linked SNX5 to systemic metabolism by showing it stabilizes insulin-degrading enzyme, with renal silencing causing insulin resistance in vivo.","evidence":"Co-IP, co-localization, in vitro and renal-selective in vivo siRNA with IDE activity and metabolic phenotyping in mice","pmids":["29080975"],"confidence":"High","gaps":["mechanism by which SNX5 stabilizes IDE not defined","whether trafficking activity of SNX5 underlies IDE regulation unresolved"]},{"year":2019,"claim":"Identified SNX5 as a negative regulator of innate antiviral signaling, acting on RIG-I ubiquitination state and the VISA-TRAF2/5 axis.","evidence":"Overexpression/knockdown with IFN-β/ISRE/NF-κB/IRF3 reporters, K48 vs K63 ubiquitination assays and VISA-TRAF2/5 co-IP","pmids":["31806368"],"confidence":"Medium","gaps":["whether SNX5 directly mediates RIG-I ubiquitination or acts via an E3 not determined","no structural or reconstitution data","single lab"]},{"year":2022,"claim":"Extended SNX5 retrograde cargo to the vesicular monoamine transporter, connecting endosome-to-TGN retrieval to AP-3-dependent dense core vesicle assembly and monoamine release.","evidence":"Loss-of-function, VMAT trafficking and DCV monoamine release assays with AP-3 genetic epistasis","pmids":["35426896"],"confidence":"High","gaps":["cargo motif on VMAT recognized by SNX5 not mapped","interplay with retromer subunits in this route unresolved"]},{"year":2023,"claim":"Defined a direct SNX5-VPS13A interaction (VAB domain to SNX5 PxP motif) that recruits the lipid-transfer protein to endosomal subdomains.","evidence":"Co-IP/pulldown, co-localization, domain mapping and pathogenic VAB mutant analysis","pmids":["36977596"],"confidence":"Medium","gaps":["functional consequence for endosomal lipid transfer not directly demonstrated","single lab"]},{"year":2024,"claim":"Established SNX5 as a required partner for CHC22-mediated Golgi-bypass GLUT4 trafficking, bridging CHC22 and the ERGIC tether p115.","evidence":"Reciprocal co-IP, domain mapping, knockdown/knockout and GLUT4 trafficking assays","pmids":["39160272"],"confidence":"High","gaps":["how SNX5 coordinates CHC22 recruitment with p115 tethering spatially unresolved","redundancy with SNX6 not fully dissected"]},{"year":2024,"claim":"Showed SNX5 binds Rab11a to promote LRP6 membrane translocation in cardiomyocytes, implicating it in cardiac hypertrophy signaling.","evidence":"Co-IP, co-localization, membrane fractionation, siRab11a epistasis and AAV9 cardiac overexpression in a TAC mouse model","pmids":["38950816"],"confidence":"Medium","gaps":["whether SNX5 directly traffics LRP6 or acts solely through Rab11a unclear","single lab"]},{"year":2024,"claim":"Demonstrated SNX5 controls actin-dependent plasma membrane remodeling and endolysosomal positioning at the B-cell immune synapse, broadening its immune role beyond macrophages.","evidence":"siRNA silencing, live-cell imaging, lysosome morphology and antigen-extraction assays","pmids":["39448266"],"confidence":"Medium","gaps":["molecular link between SNX5 and actin remodeling machinery not defined","single lab"]},{"year":2025,"claim":"Defined the ubiquitin turnover circuit setting SNX5 levels (MuRF2 degradation at K290/K324, opposed by MuRF3 and USP46) and linked SNX5 to endosomal RI-α/PKA control of myogenesis.","evidence":"SILAC/AP-MS, ubiquitination assays with lysine identification, CRISPR-KO and myogenic differentiation assays; plus USP46 deubiquitination assay with ferroptosis epistasis","pmids":["41077709","39909216"],"confidence":"High","gaps":["how SNX5 stabilizes RI-α on endosomes mechanistically unresolved","balance between MuRF2/MuRF3/USP46 in physiological contexts undefined"]},{"year":2025,"claim":"Identified SNX5-dependent recycling routes for EGFR and LRP5 that protect receptors from lysosomal degradation, sustaining EGFR and Wnt/β-catenin signaling in distinct tissue contexts.","evidence":"Loss/gain-of-function with receptor internalization/recycling and pathway readouts, plus in vivo models (EGFR/osteogenesis; LRP5/gastric cancer)","pmids":["41714616","39922976"],"confidence":"Medium","gaps":["whether the same SNX5 recycling machinery handles both receptors unresolved","cargo recognition motifs not mapped","separate single-lab studies"]},{"year":2025,"claim":"Implicated SNX5 in alpha-synuclein-induced TGN fragmentation and neuronal toxicity, where its depletion confines alpha-synuclein to early endosomes and is protective.","evidence":"Genome-wide siRNA screen with independent validation and primary neurons from transgenic mice","pmids":["40457499"],"confidence":"Medium","gaps":["mechanism connecting SNX5 trafficking to TGN fragmentation undefined","single lab"]},{"year":2025,"claim":"Provided structural insight into SNX5 cargo recognition via the NCOA7-AS antiviral isoform, whose binding motif resembles canonical SNX5/6 cargo motifs.","evidence":"Mass spectrometry pulldown, co-IP, crystal structures of NCOA7-AS/SNX5, mutagenesis and antiviral assays (preprint)","pmids":[],"confidence":"High","gaps":["preprint, not peer-reviewed","physiological consequence of NCOA7-AS recruitment by SNX5 beyond antiviral assay unresolved"]},{"year":null,"claim":"How SNX5 selects its diverse cargo (CI-MPR, VMAT, EGFR, LRP5/6, GLUT4) and toggles between retrograde, recycling, and degradative outcomes at the molecular level remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["unified cargo-recognition code across contexts not established","determinants directing retrieval-to-TGN versus plasma membrane recycling unknown","in vivo physiological hierarchy of SNX5's many roles undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,7]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,4,10,14]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,9,15]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,7,18]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,9,11]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,9,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,12,18,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,8,13]}],"complexes":["retromer/ESCPE-1 (SNX1-SNX5 / SNX5-SNX6 dimer)"],"partners":["SNX1","SNX6","DOCK180","VPS13A","CHC22","RAB11A","IDE","FANCA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y5X3","full_name":"Sorting nexin-5","aliases":[],"length_aa":404,"mass_kda":46.8,"function":"Involved in several stages of intracellular trafficking. Interacts with membranes containing phosphatidylinositol 3-phosphate (PtdIns(3P)) or phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2) (PubMed:15561769). 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). Does not have in vitro vesicle-to-membrane remodeling activity (PubMed:23085988). Involved in retrograde transport of lysosomal enzyme receptor IGF2R (PubMed:17148574, PubMed:18596235). May function as link between endosomal transport vesicles and dynactin (Probable). Plays a role in the internalization of EGFR after EGF stimulation (Probable). Involved in EGFR endosomal sorting and degradation; the function involves PIP5K1C isoform 3 and is retromer-independent (PubMed:23602387). Together with PIP5K1C isoform 3 facilitates HGS interaction with ubiquitinated EGFR, which initiates EGFR sorting to intraluminal vesicles (ILVs) of the multivesicular body for subsequent lysosomal degradation (Probable). Involved in E-cadherin sorting and degradation; inhibits PIP5K1C isoform 3-mediated E-cadherin degradation (PubMed:24610942). Plays a role in macropinocytosis (PubMed:18854019, PubMed:21048941)","subcellular_location":"Endosome; Early endosome; Early endosome membrane; Cell membrane; Cytoplasmic vesicle membrane; Cytoplasm; Cell projection, phagocytic cup; Cell projection, ruffle","url":"https://www.uniprot.org/uniprotkb/Q9Y5X3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX5","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000089006","cell_line_id":"CID000682","localizations":[{"compartment":"vesicles","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"SNX2","stoichiometry":10.0},{"gene":"SNX1","stoichiometry":10.0},{"gene":"DNAJB11","stoichiometry":0.2},{"gene":"SDF2L1","stoichiometry":0.2},{"gene":"ATP1B3","stoichiometry":0.2},{"gene":"ARID4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000682","total_profiled":1310},"omim":[{"mim_id":"621073","title":"SORTING NEXIN 32; SNX32","url":"https://www.omim.org/entry/621073"},{"mim_id":"607139","title":"FANCA GENE; FANCA","url":"https://www.omim.org/entry/607139"},{"mim_id":"606098","title":"SORTING NEXIN 6; SNX6","url":"https://www.omim.org/entry/606098"},{"mim_id":"605937","title":"SORTING NEXIN 5; SNX5","url":"https://www.omim.org/entry/605937"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNX5"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9Y5X3","domains":[{"cath_id":"3.30.1520.10","chopping":"20-176","consensus_level":"medium","plddt":89.4441,"start":20,"end":176},{"cath_id":"1.20.1270.60","chopping":"229-404","consensus_level":"medium","plddt":94.7727,"start":229,"end":404}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5X3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5X3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5X3-F1-predicted_aligned_error_v6.png","plddt_mean":87.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNX5","jax_strain_url":"https://www.jax.org/strain/search?query=SNX5"},"sequence":{"accession":"Q9Y5X3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y5X3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y5X3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5X3"}},"corpus_meta":[{"pmid":"17148574","id":"PMC_17148574","title":"A loss-of-function screen reveals SNX5 and SNX6 as potential components of the mammalian retromer.","date":"2006","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17148574","citation_count":213,"is_preprint":false},{"pmid":"10600472","id":"PMC_10600472","title":"SNX5, a new member of the sorting nexin family, binds to the Fanconi anemia complementation group A protein.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10600472","citation_count":53,"is_preprint":false},{"pmid":"18854019","id":"PMC_18854019","title":"A role for SNX5 in the regulation of macropinocytosis.","date":"2008","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18854019","citation_count":50,"is_preprint":false},{"pmid":"23213485","id":"PMC_23213485","title":"SNX5 is essential for efficient macropinocytosis and antigen processing in primary macrophages.","date":"2012","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/23213485","citation_count":33,"is_preprint":false},{"pmid":"25645681","id":"PMC_25645681","title":"miR-216a regulates snx5, a novel notch signaling pathway component, during zebrafish retinal development.","date":"2015","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/25645681","citation_count":30,"is_preprint":false},{"pmid":"18596235","id":"PMC_18596235","title":"The DHR1 domain of DOCK180 binds to SNX5 and regulates cation-independent mannose 6-phosphate receptor transport.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18596235","citation_count":29,"is_preprint":false},{"pmid":"33982667","id":"PMC_33982667","title":"Exosomal circRNA 0001445 promotes glioma progression through miRNA-127-5p/SNX5 pathway.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33982667","citation_count":25,"is_preprint":false},{"pmid":"16857196","id":"PMC_16857196","title":"Snx5, as a Mind bomb-binding protein, is expressed in hematopoietic and endothelial precursor cells in zebrafish.","date":"2006","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16857196","citation_count":23,"is_preprint":false},{"pmid":"35024436","id":"PMC_35024436","title":"SNX5 suppresses clear cell renal cell carcinoma progression by inducing CD44 internalization and epithelial-to-mesenchymal transition.","date":"2021","source":"Molecular therapy oncolytics","url":"https://pubmed.ncbi.nlm.nih.gov/35024436","citation_count":22,"is_preprint":false},{"pmid":"29080975","id":"PMC_29080975","title":"Loss of renal SNX5 results in impaired IDE activity and insulin resistance in mice.","date":"2017","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/29080975","citation_count":19,"is_preprint":false},{"pmid":"35426896","id":"PMC_35426896","title":"SNX5 targets a monoamine transporter to the TGN for assembly into dense core vesicles by AP-3.","date":"2022","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35426896","citation_count":9,"is_preprint":false},{"pmid":"36977596","id":"PMC_36977596","title":"The association of lipid transfer protein VPS13A with endosomes is mediated by sorting nexin SNX5.","date":"2023","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/36977596","citation_count":8,"is_preprint":false},{"pmid":"31806368","id":"PMC_31806368","title":"SNX5 inhibits RLR-mediated antiviral signaling by targeting RIG-I-VISA signalosome.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31806368","citation_count":6,"is_preprint":false},{"pmid":"36528556","id":"PMC_36528556","title":"Overexpression of lncRNA HOXA-AS2 promotes the progression of oral squamous cell carcinoma by mediating SNX5 expression.","date":"2022","source":"BMC molecular and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/36528556","citation_count":5,"is_preprint":false},{"pmid":"39160272","id":"PMC_39160272","title":"CHC22 clathrin recruitment to the early secretory pathway requires two-site interaction with SNX5 and p115.","date":"2024","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/39160272","citation_count":3,"is_preprint":false},{"pmid":"39155279","id":"PMC_39155279","title":"Noncanonical formation of SNX5 gene-derived circular RNA regulates cancer growth.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39155279","citation_count":3,"is_preprint":false},{"pmid":"39448266","id":"PMC_39448266","title":"SNX5 promotes antigen presentation in B cells by dual regulation of actin and lysosomal dynamics.","date":"2024","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/39448266","citation_count":3,"is_preprint":false},{"pmid":"38950816","id":"PMC_38950816","title":"SNX5-Rab11a protects against cardiac hypertrophy through regulating LRP6 membrane translocation.","date":"2024","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/38950816","citation_count":2,"is_preprint":false},{"pmid":"39922976","id":"PMC_39922976","title":"SNX5 facilitates the progression of gastric cancer by increasing the membrane localization of LRP5.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/39922976","citation_count":2,"is_preprint":false},{"pmid":"39020492","id":"PMC_39020492","title":"Moxibustion improves motor function by down-regulating SNX5 and inhibiting ferroptosis in neurons of corpus striatum in mice with Parkinson's disease.","date":"2024","source":"Zhen ci yan jiu = Acupuncture research","url":"https://pubmed.ncbi.nlm.nih.gov/39020492","citation_count":2,"is_preprint":false},{"pmid":"40457499","id":"PMC_40457499","title":"A genome-wide RNA interference screening reveals protectiveness of SNX5 knockdown in a Parkinson's disease cell model.","date":"2025","source":"Translational neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/40457499","citation_count":1,"is_preprint":false},{"pmid":"41077709","id":"PMC_41077709","title":"The Novel MuRF2 Target SNX5 Regulates PKA Activity Through Stabilization of RI-α and Controls Myogenic Differentiation.","date":"2025","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/41077709","citation_count":1,"is_preprint":false},{"pmid":"39909216","id":"PMC_39909216","title":"Heliox alleviates ischemia-reperfusion-induced damage to neuronal cells by repressing the USP46-SNX5 Axis-triggered ferroptosis.","date":"2025","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/39909216","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":"42028750","id":"PMC_42028750","title":"Hypermethylation‑induced silencing of ITGA4 promotes oral squamous cell carcinoma progression through SNX5 upregulation.","date":"2026","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/42028750","citation_count":0,"is_preprint":false},{"pmid":"41714616","id":"PMC_41714616","title":"Implantation awakens peri-implant osteogenic potential via Snx5-EGFR axis-mediated mechanical transduction.","date":"2026","source":"International journal of oral science","url":"https://pubmed.ncbi.nlm.nih.gov/41714616","citation_count":0,"is_preprint":false},{"pmid":"42178051","id":"PMC_42178051","title":"Acacetin targets SNX5 to promote autophagy degradation of NLRP3 inflammasome against cognitive impairment in Alzheimer's disease.","date":"2026","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/42178051","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},{"pmid":null,"id":"bio_10.1101_2025.04.01.646557","title":"SNX-BAR proteins 5 and 6 are required for NCOA7-AS antiviral activity against influenza A virus","date":"2025-04-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.01.646557","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17810,"output_tokens":5875,"usd":0.070777,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14467,"output_tokens":5677,"usd":0.10713,"stage2_stop_reason":"end_turn"},"total_usd":0.177907,"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\": 2006,\n      \"finding\": \"SNX5 and SNX6 are required for retromer-mediated endosome-to-trans-Golgi-network retrieval of the cation-independent mannose-6-phosphate receptor (CI-MPR); RNAi knockdown of SNX5 or SNX6 induced a phenotype similar to suppression of known retromer components. SNX5 co-localizes with SNX1 on early endosomes, but unlike SNX6, SNX5 did not appear to form a complex with SNX1 by immunoprecipitation. Suppression of SNX5 and/or SNX6 resulted in significant post-translational loss of SNX1.\",\n      \"method\": \"RNAi loss-of-function screen, immunoprecipitation, co-localization imaging\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic RNAi screen with defined functional readout (CI-MPR trafficking), co-localization and immunoprecipitation, multiple retromer components tested as controls\",\n      \"pmids\": [\"17148574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SNX5 binds to the Fanconi anemia complementation group A (FANCA) protein; the interaction was identified by yeast two-hybrid and confirmed by immunoprecipitation. The PX domain of SNX5 is not required for this binding. Overexpression of SNX5 increased FANCA protein levels.\",\n      \"method\": \"Yeast two-hybrid screen, immunoprecipitation, deletion mutant analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by co-IP and deletion mapping, single lab\",\n      \"pmids\": [\"10600472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SNX5 promotes macropinocytosis; it is recruited to newly-formed macropinosomes and to EGF receptor-positive plasma membrane regions. Stable overexpression of GFP-SNX5 in HEK cells approximately doubled constitutive and EGF-stimulated macropinosome formation. SNX5 PX domain binds specifically PtdIns(3)P and PtdIns(3,4)P2, and inhibition of EGF receptor tyrosine kinase (AG1478) prevented SNX5 recruitment to the plasma membrane.\",\n      \"method\": \"Live-cell imaging, stable GFP-SNX5 expression, phosphoinositide-binding assays, EGF receptor inhibitor treatment, macropinosome quantification\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined functional phenotype with multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"18854019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SNX5 is essential for macropinosome biogenesis in primary macrophages and for antigen uptake/processing. Depletion of SNX5 in bone marrow-derived macrophages dramatically reduced macropinosome number and size and reduced uptake and processing of soluble ovalbumin. SNX1 knockout had no effect on SNX5 localization or macropinosome biogenesis, demonstrating SNX5 can function independently of SNX1.\",\n      \"method\": \"siRNA knockdown in primary macrophages, SNX1 knockout mice, fluorescence microscopy, ovalbumin uptake assay\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — primary cell knockdown and knockout model with defined functional readouts, replicated in two genetic settings\",\n      \"pmids\": [\"23213485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The DHR1 domain of DOCK180 interacts with SNX5 (and SNX1, 2, 6); SNX5 was the most efficiently co-immunoprecipitated among these. DOCK180 co-localizes with SNX5 at endosomes. RNAi knockdown of SNX5 or DOCK180 (but not Rac1) caused redistribution of CI-MPR from TGN to endosomes. Expression of the DHR1 domain alone was sufficient to restore CI-MPR distribution in DOCK180 knockdown cells, indicating DOCK180 regulates CI-MPR trafficking via SNX5 independently of its GEF activity.\",\n      \"method\": \"LC-MS/MS pulldown, co-immunoprecipitation, co-localization imaging, RNAi knockdown, CI-MPR trafficking assay, domain rescue experiment\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, mass spectrometry identification, domain rescue, multiple functional readouts in one study\",\n      \"pmids\": [\"18596235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Zebrafish Snx5 is a binding partner of the E3 ubiquitin ligase Mind bomb (Mib); Snx5 co-localizes with Mind bomb in early endosomal compartments. Morpholino knockdown of snx5 caused defects in hematopoiesis and blood vessel development in zebrafish embryos.\",\n      \"method\": \"Yeast two-hybrid, co-localization imaging, morpholino knockdown in zebrafish\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid interaction confirmed by co-localization with in vivo loss-of-function phenotype, single lab\",\n      \"pmids\": [\"16857196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In zebrafish retinal development, SNX5 co-localizes with Mind bomb and Delta complexes and directly binds Mib. SNX5 functions downstream of miR-216a to regulate Notch signaling: knockdown of snx5 decreased Notch activation, whereas overexpression of snx5 increased it, placing SNX5 as a positive component of the Notch pathway through promoting endocytosis of Delta.\",\n      \"method\": \"co-localization, direct binding (co-IP), morpholino knockdown, snx5 overexpression, Notch signaling reporters in zebrafish\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (gain- and loss-of-function with defined Notch pathway readout), single lab\",\n      \"pmids\": [\"25645681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Renal SNX5 co-localizes and co-immunoprecipitates with insulin-degrading enzyme (IDE) at the plasma membrane and perinuclear area of human renal proximal tubule cells; insulin stimulation increases their co-localization and co-immunoprecipitation. Silencing SNX5 in cultured cells and in mouse kidney decreased IDE expression and activity, leading to insulin resistance and elevated blood glucose and insulin in vivo.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, siRNA silencing in cells, renal-selective siRNA delivery via osmotic mini-pump in mice, IDE activity assay, metabolic phenotyping\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (co-IP, co-localization, in vitro silencing, in vivo silencing with functional metabolic readout), replicated in rat and mouse models\",\n      \"pmids\": [\"29080975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNX5 negatively regulates RLR-mediated antiviral signaling: overexpression of SNX5 inhibited virus-induced IFN-β promoter, ISRE, NF-κB, and IRF3 activation, while SNX5 knockdown had the opposite effect. SNX5 overexpression promoted K48-linked (degradative) ubiquitination and reduced K63-linked ubiquitination of RIG-I, reducing RIG-I protein levels. SNX5 overexpression also weakened the VISA-TRAF2/5 interaction.\",\n      \"method\": \"Overexpression and RNAi knockdown, luciferase reporter assays for IFN-β/ISRE/NF-κB/IRF3, ubiquitination assay (K48 vs K63), co-immunoprecipitation of VISA-TRAF2/5\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple reporter and biochemical assays in single lab, no structural or in vitro reconstitution\",\n      \"pmids\": [\"31806368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SNX5 mediates retrograde transport of the vesicular monoamine transporter (VMAT) from endosomes to the TGN, which is required for AP-3-dependent assembly of VMAT into dense core vesicles (DCVs). Loss of SNX5 disrupts VMAT trafficking to DCVs and impairs regulated monoamine release.\",\n      \"method\": \"SNX5 loss-of-function, VMAT trafficking assay, DCV monoamine release assay, genetic interaction with AP-3\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined cargo (VMAT) and organelle (TGN/DCV) with loss-of-function phenotype, functional monoamine release assay, genetic epistasis with AP-3\",\n      \"pmids\": [\"35426896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SNX5 interacts with VPS13A via the VPS13 adaptor-binding (VAB) domain of VPS13A and a PxP motif in SNX5 (analogous to yeast Ypt35-Vps13 interaction). This interaction mediates VPS13A association with endosomal subdomains. A pathogenic asparagine mutation in the VAB domain impairs this interaction.\",\n      \"method\": \"Co-immunoprecipitation/pulldown, co-localization, domain mapping, mutant analysis\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction mapping with domain and pathogenic mutation validation, single lab\",\n      \"pmids\": [\"36977596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CHC22 clathrin C-terminal trimerization domain interacts with SNX5 (and functionally redundant SNX6), and this interaction is required for CHC22 recruitment to ERGIC membranes. SNX5 also binds the ERGIC tether p115. Both the CHC22-SNX5 and CHC22-p115 interactions are required for CHC22-mediated Golgi-bypass trafficking of GLUT4 to the intracellular GLUT4 storage compartment; disruption of either interaction inhibits GLUT4 targeting.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, GLUT4 trafficking assay, CHC22/SNX5/SNX6 knockdown/knockout, localization imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with domain mapping, loss-of-function studies for both interaction partners, defined cargo (GLUT4) and organelle trafficking readout\",\n      \"pmids\": [\"39160272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNX5 directly binds Rab11a in cardiomyocytes, increasing Rab11a membrane accumulation. This SNX5-Rab11a interaction promotes membrane translocation of LRP6, a regulator of cardiac hypertrophy. siRNA silencing of Rab11a abolished the LRP6 membrane accumulation induced by SNX5 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence co-localization, membrane protein fractionation, siRNA knockdown, AAV9-mediated cardiac-specific overexpression in TAC mouse model, echocardiography\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, co-localization, and epistasis (siRab11a) with in vivo cardiac model; single lab\",\n      \"pmids\": [\"38950816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNX5 regulates actin-dependent plasma membrane remodeling in B cells and endolysosomal trafficking at the immune synapse. SNX5-depleted B cells showed enlarged lysosomes not recruited to the synaptic membrane, reducing antigen extraction and presentation capacity.\",\n      \"method\": \"siRNA silencing, live-cell imaging, lysosome morphology analysis, antigen extraction assay at immune synapse\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (lysosome recruitment, antigen presentation), multiple imaging-based readouts, single lab\",\n      \"pmids\": [\"39448266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX5 is a substrate of the E3 ubiquitin ligase MuRF2, which ubiquitinates SNX5 at lysines 290 and 324, leading to its proteasomal degradation. MuRF3 counteracts this effect. SNX5 stabilizes PKA regulatory subunit RI-α within early endosomes; SNX5 knockout reduced RI-α stability, enhanced PKA activity, increased HDAC5 degradation, and upregulated myostatin via MEF2, impairing myogenic differentiation. Both coiled-coil domains of MuRF3 and the BAR domain of SNX5 mediate the MuRF2/3-SNX5 interaction.\",\n      \"method\": \"SILAC/AP-MS, co-immunoprecipitation, domain mapping, ubiquitination assay with K290/324 site identification, CRISPR-KO, siRNA, endosome isolation, mass spectrometry of endosomal cargo, myogenic differentiation assays\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ubiquitination assay with specific lysine identification, mass spectrometry cargo identification, CRISPR-KO with multiple functional readouts, domain mapping, multiple orthogonal methods in one study\",\n      \"pmids\": [\"41077709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX5 knockdown protects neurons from alpha-synuclein-induced toxicity. Extracellular or overexpressed intracellular alpha-synuclein caused fragmentation of the trans-Golgi network, which was prevented by SNX5 knockdown; SNX5 knockdown confined alpha-synuclein to early endosomes. This was confirmed in primary neurons from transgenic mice.\",\n      \"method\": \"Genome-wide siRNA screen, independent siRNA validation, immunofluorescence microscopy, primary neuron culture from transgenic mice, qPCR, Western blot\",\n      \"journal\": \"Translational neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated genome-wide screen hit confirmed in primary neurons with defined mechanistic readout (TGN fragmentation, alpha-synuclein compartmentalization), single lab\",\n      \"pmids\": [\"40457499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX5 interacts directly with NCOA7-AS (the short antiviral isoform of NCOA7). Crystal structures of NCOA7-AS/SNX5 complexes revealed that the SNX5-interaction motif in NCOA7-AS resembles known cargo motifs recognized by SNX5/6. Specific critical residues at the interface were identified as important for binding and antiviral activity against influenza A virus. SNX5 (and SNX6) are essential for NCOA7-AS antiviral activity.\",\n      \"method\": \"Mass spectrometry pulldown (NCOA7-AS partners), co-IP, crystal structure determination, site-directed mutagenesis, antiviral activity assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutagenesis and functional validation (antiviral assay), single lab preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Molecular dynamics and metadynamics simulations of SNX1-SNX5 heterodimer on membranes show that SNX5-PXD interacts with the CI-MPR cargo tail via aromatic (π-π) interactions, with a favorable binding free energy. SNX1-PXD provides robust membrane binding largely insensitive to mutation of basic residues. These computational models, benchmarked against available cryo-EM structures of SNX1 homodimer and SNX1-SNX5 heterodimer, support a division of labor: SNX1 handles membrane curvature/binding and SNX5 handles cargo recognition.\",\n      \"method\": \"All-atom molecular dynamics, metadynamics simulations, continuum mechanics (DTS) mesoscopic simulation, benchmarking against cryo-EM structures\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational predictions only, no direct experimental validation of binding in this paper\",\n      \"pmids\": [\"41206513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX5 facilitates recycling of phosphorylated EGFR (p-EGFR) back to the plasma membrane to sustain EGFR signaling; loss of SNX5 redirects EGFR trafficking toward late endosomes and lysosomal degradation, thereby attenuating EGFR signaling and mechanosensitive osteogenic differentiation.\",\n      \"method\": \"Multi-dataset screening, functional loss-of-function studies, EGFR trafficking assay, in vivo SNX5-deficient model with implant placement\",\n      \"journal\": \"International journal of oral science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cargo (EGFR) and trafficking readout plus in vivo model, single lab\",\n      \"pmids\": [\"41714616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP46 deubiquitinates SNX5, increasing its stability. SNX5 knockdown abolished the ferroptosis-promoting effect of USP46 in ischemia-reperfusion-treated neuronal cells, placing SNX5 downstream of USP46 in a ferroptosis-promoting pathway.\",\n      \"method\": \"Mass spectrometry (USP46 interactors), co-immunoprecipitation, deubiquitination assay, SNX5 siRNA knockdown, ferroptosis assays, in vivo rat I/R model\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and deubiquitination assay with epistasis (SNX5 KD rescues USP46 OE phenotype), single lab\",\n      \"pmids\": [\"39909216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX5 interacts with LRP5 in gastric cancer cells; SNX5 inhibits LRP5 internalization and promotes its recycling to the cell membrane, preventing lysosomal degradation of LRP5. Increased membrane LRP5 facilitates β-catenin stabilization and Wnt pathway activation.\",\n      \"method\": \"Co-immunoprecipitation, LRP5 internalization/recycling assay, β-catenin stabilization assay, SNX5 knockdown/overexpression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction shown by co-IP, receptor trafficking assay with functional pathway readout, single lab\",\n      \"pmids\": [\"39922976\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNX5 is a BAR-PX domain sorting nexin that functions on early endosomes and the TGN as a multifunctional trafficking regulator: it forms heterodimers (primarily with SNX1 or SNX6 as part of the retromer/ESCPE-1 machinery) to mediate retrograde endosome-to-TGN retrieval of cargo including CI-MPR and VMAT; its PX domain binds PtdIns(3)P and PtdIns(3,4)P2 to direct membrane recruitment; it promotes macropinocytosis, antigen presentation in macrophages and B cells, and Notch pathway activation (via Mind bomb endocytosis); it interacts with and stabilizes IDE (regulating insulin metabolism), with VPS13A (mediating endosomal lipid transfer), with Rab11a (promoting LRP6/LRP5 membrane recycling), with FANCA, and with DOCK180 (linking GEF-independent CI-MPR trafficking); it is ubiquitinated by MuRF2 at K290/K324 for proteasomal degradation (counteracted by MuRF3), and is deubiquitinated/stabilized by USP46; it is required for CHC22-mediated Golgi-bypass GLUT4 trafficking via interaction with both CHC22 and p115 at the ERGIC; and it negatively regulates innate antiviral signaling by promoting degradative K48-ubiquitination of RIG-I and disrupting the VISA-TRAF2/5 interaction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNX5 is a BAR-PX domain sorting nexin that governs endosomal cargo sorting and membrane remodeling, functioning both within retromer/retrograde machinery and in independent trafficking routes [#0, #4]. Its PX domain binds PtdIns(3)P and PtdIns(3,4)P2 to direct membrane recruitment, and it promotes macropinosome biogenesis at EGF receptor-positive plasma membrane regions [#2]. In retrograde transport, SNX5 (cooperating with SNX6) is required for endosome-to-TGN retrieval of CI-MPR and of the vesicular monoamine transporter, the latter feeding AP-3-dependent dense core vesicle assembly and regulated monoamine release [#0, #9]; within the SNX1-SNX5 dimer, SNX5 contributes cargo recognition through its PX domain [#17]. SNX5 directs cargo recycling to the plasma membrane, sustaining EGFR signaling by diverting receptors from lysosomal degradation [#18] and, via interaction with Rab11a and LRP6/LRP5, promoting receptor membrane accumulation and Wnt/β-catenin activation [#12, #20]. It is essential for macropinocytosis and antigen uptake/processing in macrophages, and for endolysosomal trafficking and membrane remodeling at the B-cell immune synapse [#3, #13]. SNX5 additionally serves as a protein-interaction hub: it stabilizes insulin-degrading enzyme to control insulin metabolism in renal cells [#7], binds the E3 ligase Mind bomb to drive Delta endocytosis and Notch activation [#5, #6], associates with VPS13A to recruit it to endosomal subdomains [#10], and partners with CHC22 clathrin and the tether p115 at the ERGIC to enable Golgi-bypass GLUT4 trafficking [#11]. SNX5 negatively regulates RIG-I-mediated antiviral signaling by promoting K48-linked degradative ubiquitination of RIG-I and weakening the VISA-TRAF2/5 interaction [#8]. SNX5 abundance is set by ubiquitin turnover: MuRF2 ubiquitinates it at K290/K324 for proteasomal degradation (counteracted by MuRF3), while USP46 deubiquitinates and stabilizes it; through endosomal stabilization of the PKA regulatory subunit RI-α, SNX5 modulates myogenic differentiation [#14, #19].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the first SNX5 binding partner, linking it to the Fanconi anemia protein FANCA and to protein stabilization, before its endosomal role was defined.\",\n      \"evidence\": \"Yeast two-hybrid screen with co-IP and deletion mapping in human cells\",\n      \"pmids\": [\"10600472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PX domain dispensable for binding but functional consequence of the interaction unresolved\", \"single lab, no in vivo validation\", \"no connection drawn to later-defined trafficking roles\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed SNX5 in the retromer pathway by showing it is required for endosome-to-TGN retrieval of CI-MPR, defining its core trafficking function.\",\n      \"evidence\": \"RNAi loss-of-function screen with CI-MPR trafficking readout, co-localization and IP in mammalian cells\",\n      \"pmids\": [\"17148574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SNX5 did not co-IP with SNX1 unlike SNX6, leaving dimerization partner ambiguous\", \"mechanism of SNX1 stabilization by SNX5/SNX6 not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected SNX5 to developmental signaling by identifying Mind bomb as a partner and showing loss-of-function disrupts hematopoiesis and vasculogenesis in vivo.\",\n      \"evidence\": \"Yeast two-hybrid, co-localization and morpholino knockdown in zebrafish\",\n      \"pmids\": [\"16857196\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanistic link between Mind bomb binding and developmental phenotype not yet defined\", \"single model organism\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the membrane-recruitment logic of SNX5, showing its PX domain selects PtdIns(3)P/PtdIns(3,4)P2 and that it actively drives macropinosome formation downstream of EGFR.\",\n      \"evidence\": \"Live-cell imaging, phosphoinositide-binding assays and EGFR inhibitor treatment with macropinosome quantification\",\n      \"pmids\": [\"18854019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"how EGFR activity drives SNX5 plasma membrane recruitment mechanistically unresolved\", \"performed in overexpression HEK system\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed a GEF-independent role for DOCK180 in CI-MPR trafficking acting through SNX5, expanding the partner network controlling retrograde sorting.\",\n      \"evidence\": \"LC-MS/MS pulldown, reciprocal co-IP, RNAi and DHR1 domain rescue of CI-MPR distribution\",\n      \"pmids\": [\"18596235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how DOCK180-SNX5 binding controls cargo selection mechanistically unclear\", \"Rac1-independence shown but downstream effectors undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated SNX5 is essential for macropinocytosis and antigen processing in primary macrophages and can act independently of SNX1, distinguishing its function from its dimer partner.\",\n      \"evidence\": \"siRNA knockdown in primary macrophages, SNX1-knockout mice, ovalbumin uptake/processing assays\",\n      \"pmids\": [\"23213485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"partner(s) supporting SNX1-independent function not identified\", \"molecular basis of macropinosome size/number control unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Positioned SNX5 as a positive Notch pathway component acting downstream of miR-216a by promoting Delta endocytosis via Mind bomb.\",\n      \"evidence\": \"Co-localization, co-IP, morpholino loss- and gain-of-function with Notch reporters in zebrafish retina\",\n      \"pmids\": [\"25645681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"how SNX5-Mib binding mechanically drives Delta internalization not shown\", \"single developmental context\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked SNX5 to systemic metabolism by showing it stabilizes insulin-degrading enzyme, with renal silencing causing insulin resistance in vivo.\",\n      \"evidence\": \"Co-IP, co-localization, in vitro and renal-selective in vivo siRNA with IDE activity and metabolic phenotyping in mice\",\n      \"pmids\": [\"29080975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism by which SNX5 stabilizes IDE not defined\", \"whether trafficking activity of SNX5 underlies IDE regulation unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified SNX5 as a negative regulator of innate antiviral signaling, acting on RIG-I ubiquitination state and the VISA-TRAF2/5 axis.\",\n      \"evidence\": \"Overexpression/knockdown with IFN-β/ISRE/NF-κB/IRF3 reporters, K48 vs K63 ubiquitination assays and VISA-TRAF2/5 co-IP\",\n      \"pmids\": [\"31806368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether SNX5 directly mediates RIG-I ubiquitination or acts via an E3 not determined\", \"no structural or reconstitution data\", \"single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended SNX5 retrograde cargo to the vesicular monoamine transporter, connecting endosome-to-TGN retrieval to AP-3-dependent dense core vesicle assembly and monoamine release.\",\n      \"evidence\": \"Loss-of-function, VMAT trafficking and DCV monoamine release assays with AP-3 genetic epistasis\",\n      \"pmids\": [\"35426896\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"cargo motif on VMAT recognized by SNX5 not mapped\", \"interplay with retromer subunits in this route unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a direct SNX5-VPS13A interaction (VAB domain to SNX5 PxP motif) that recruits the lipid-transfer protein to endosomal subdomains.\",\n      \"evidence\": \"Co-IP/pulldown, co-localization, domain mapping and pathogenic VAB mutant analysis\",\n      \"pmids\": [\"36977596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"functional consequence for endosomal lipid transfer not directly demonstrated\", \"single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established SNX5 as a required partner for CHC22-mediated Golgi-bypass GLUT4 trafficking, bridging CHC22 and the ERGIC tether p115.\",\n      \"evidence\": \"Reciprocal co-IP, domain mapping, knockdown/knockout and GLUT4 trafficking assays\",\n      \"pmids\": [\"39160272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how SNX5 coordinates CHC22 recruitment with p115 tethering spatially unresolved\", \"redundancy with SNX6 not fully dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed SNX5 binds Rab11a to promote LRP6 membrane translocation in cardiomyocytes, implicating it in cardiac hypertrophy signaling.\",\n      \"evidence\": \"Co-IP, co-localization, membrane fractionation, siRab11a epistasis and AAV9 cardiac overexpression in a TAC mouse model\",\n      \"pmids\": [\"38950816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether SNX5 directly traffics LRP6 or acts solely through Rab11a unclear\", \"single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated SNX5 controls actin-dependent plasma membrane remodeling and endolysosomal positioning at the B-cell immune synapse, broadening its immune role beyond macrophages.\",\n      \"evidence\": \"siRNA silencing, live-cell imaging, lysosome morphology and antigen-extraction assays\",\n      \"pmids\": [\"39448266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"molecular link between SNX5 and actin remodeling machinery not defined\", \"single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the ubiquitin turnover circuit setting SNX5 levels (MuRF2 degradation at K290/K324, opposed by MuRF3 and USP46) and linked SNX5 to endosomal RI-α/PKA control of myogenesis.\",\n      \"evidence\": \"SILAC/AP-MS, ubiquitination assays with lysine identification, CRISPR-KO and myogenic differentiation assays; plus USP46 deubiquitination assay with ferroptosis epistasis\",\n      \"pmids\": [\"41077709\", \"39909216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how SNX5 stabilizes RI-α on endosomes mechanistically unresolved\", \"balance between MuRF2/MuRF3/USP46 in physiological contexts undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified SNX5-dependent recycling routes for EGFR and LRP5 that protect receptors from lysosomal degradation, sustaining EGFR and Wnt/β-catenin signaling in distinct tissue contexts.\",\n      \"evidence\": \"Loss/gain-of-function with receptor internalization/recycling and pathway readouts, plus in vivo models (EGFR/osteogenesis; LRP5/gastric cancer)\",\n      \"pmids\": [\"41714616\", \"39922976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether the same SNX5 recycling machinery handles both receptors unresolved\", \"cargo recognition motifs not mapped\", \"separate single-lab studies\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated SNX5 in alpha-synuclein-induced TGN fragmentation and neuronal toxicity, where its depletion confines alpha-synuclein to early endosomes and is protective.\",\n      \"evidence\": \"Genome-wide siRNA screen with independent validation and primary neurons from transgenic mice\",\n      \"pmids\": [\"40457499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism connecting SNX5 trafficking to TGN fragmentation undefined\", \"single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided structural insight into SNX5 cargo recognition via the NCOA7-AS antiviral isoform, whose binding motif resembles canonical SNX5/6 cargo motifs.\",\n      \"evidence\": \"Mass spectrometry pulldown, co-IP, crystal structures of NCOA7-AS/SNX5, mutagenesis and antiviral assays (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"preprint, not peer-reviewed\", \"physiological consequence of NCOA7-AS recruitment by SNX5 beyond antiviral assay unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SNX5 selects its diverse cargo (CI-MPR, VMAT, EGFR, LRP5/6, GLUT4) and toggles between retrograde, recycling, and degradative outcomes at the molecular level remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"unified cargo-recognition code across contexts not established\", \"determinants directing retrieval-to-TGN versus plasma membrane recycling unknown\", \"in vivo physiological hierarchy of SNX5's many roles undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 4, 10, 14]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 9, 15]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 7, 18]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 9, 11]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 9, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 12, 18, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 8, 13]}\n    ],\n    \"complexes\": [\"retromer/ESCPE-1 (SNX1-SNX5 / SNX5-SNX6 dimer)\"],\n    \"partners\": [\"SNX1\", \"SNX6\", \"DOCK180\", \"VPS13A\", \"CHC22\", \"RAB11A\", \"IDE\", \"FANCA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}