{"gene":"VPS26B","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2007,"finding":"Crystal structure of mouse Vps26B was determined, revealing a striking structural similarity to the arrestin family of proteins. Structure-based mutagenesis showed that both Vps26A and Vps26B are incorporated into retromer complexes through binding of Vps35 to a highly conserved surface patch within the C-terminal subdomain, and this interaction is required for endosomal recruitment of the proteins.","method":"X-ray crystallography, structure-based mutagenesis, biochemical binding assays","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional validation of endosomal recruitment","pmids":["18088321"],"is_preprint":false},{"year":2007,"finding":"Both Vps26A and Vps26B bind to Vps35/Vps29 with nanomolar affinity and compete for a single binding site, defining distinct retromer complexes in vitro and in vivo.","method":"In vitro binding assays (affinity measurements), competition assays, co-immunoprecipitation","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — quantitative in vitro binding and in vivo co-IP in same study, replicated by subsequent papers","pmids":["18088321"],"is_preprint":false},{"year":2005,"finding":"Vps26B is a peripheral membrane protein that co-precipitates with Vps35 from transfected cells; direct interaction was confirmed by yeast two-hybrid analysis, establishing Vps26B as a subunit of the retromer complex. In HeLa cells, Vps26B localizes to cytoplasm with low levels at the plasma membrane (distinct from Vps26A which is predominantly endosomal). In A549 cells, Vps26B co-localizes with actin-rich lamellipodia. TIRF microscopy confirmed plasma membrane association of CFP-Vps26B in HEK293 cells.","method":"Co-immunoprecipitation, yeast two-hybrid, subcellular fractionation, fluorescence microscopy, TIRF microscopy","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple orthogonal methods (Co-IP, Y2H, live imaging) in single lab establishing protein-protein interaction and distinct localization","pmids":["16190980"],"is_preprint":false},{"year":2011,"finding":"Vps26B-retromer associates with TBC1D5 and GOLPH3 (like Vps26A-retromer), but unlike Vps26A-retromer, Vps26B-retromer does not interact with CI-M6PR, leading to degradation of this receptor and increased cathepsin D secretion. Deletion of the variable Vps26B C-terminal region restores CI-M6PR cycling, indicating that this region directly controls differential cargo selection between the two paralogous retromer complexes.","method":"Co-immunoprecipitation, stable cell lines (HEK293 expressing Vps26A-myc or Vps26B-myc), deletion mutagenesis, receptor trafficking assays, secretion assays","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, deletion mutagenesis with rescue, functional cargo-sorting readouts; replicated finding from same group with orthogonal methods","pmids":["21920005"],"is_preprint":false},{"year":2010,"finding":"Vps26b knockout mice lack the Vps26b-Vps29-Vps35 retromer complex and show a severe reduction of Vps35 protein, while the Vps26a-Vps29-Vps35 complex remains intact. Sortilin protein levels are increased approximately 20% in Vps26b-deficient mice, implicating Vps26b-Vps29-Vps35 retromer in sortilin transport from endosomes to the TGN.","method":"Vps26b knockout mice, Western blot, co-immunoprecipitation, protein level quantification","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with specific molecular and cargo phenotype, single lab","pmids":["21040701"],"is_preprint":false},{"year":2008,"finding":"In mouse testis, Vps26b forms a Vps26b-Vps29-Vps35 retromer complex that is distinct from the Vps26a-Vps29-Vps35 and Vps26aT-Vps29-Vps35 complexes; direct interaction of Vps26b with Vps35 was demonstrated by immunoprecipitation and pull-down assay.","method":"Immunoprecipitation, pull-down assay, Western blot, RT-PCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and pull-down, replicated interaction finding from prior studies in a tissue-specific context","pmids":["18656452"],"is_preprint":false},{"year":2019,"finding":"Murine cytomegalovirus M45 protein recruits VPS26B and the LC3-interacting adaptor protein TBC1D5 to facilitate degradation of NEMO and RIPK1 protein aggregates by selective autophagy (aggrephagy), revealing VPS26B as a component of the aggrephagy machinery exploited for viral immune evasion.","method":"Co-immunoprecipitation, protein aggregation assays, autophagy/degradation assays, mutagenesis of M45 aggregation motif","journal":"Nature microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and functional degradation assays in single study; VPS26B role defined mechanistically within aggrephagy pathway","pmids":["31844296"],"is_preprint":false},{"year":2021,"finding":"NEK1 kinase regulates retromer-mediated endosomal trafficking by directly phosphorylating VPS26B. NEK1 deficiency disrupts endosomal trafficking of plasma membrane proteins, and genetic inactivation of RIPK1 can rescue postnatal lethality and blood-brain barrier damage in NEK1-deficient mice.","method":"Kinase assay (phosphorylation of VPS26B by NEK1), genetic epistasis (NEK1 KO with RIPK1 inactivation rescue), endosomal trafficking assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation demonstrated and genetic rescue confirms pathway position, single lab study","pmids":["34376696"],"is_preprint":false},{"year":2015,"finding":"Vps26B-retromer negatively regulates plasma membrane resensitization of PAR-2 (a protease-activated G protein-coupled receptor). Overexpression of Vps26B causes a significant delay in plasma membrane repopulation of PAR-2 following receptor stimulation, resulting in impaired PAR-2 activation after resensitization, without affecting initial receptor activation, ERK1/2 signaling, or endocytosis.","method":"Stable HEK293 cell line expressing Vps26B, calcium release assays, ERK1/2 signaling assays, receptor trafficking/resensitization assays","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional receptor trafficking assays with defined phenotypic readouts, single lab","pmids":["26113136"],"is_preprint":false},{"year":2021,"finding":"Neurons are enriched with a VPS26B-organized retromer core that is differentially dedicated to endosomal recycling. VPS26B regulates glutamate receptor and SORL1 recycling, and its depletion causes synaptic dysfunction particularly in the trans-entorhinal cortex.","method":"Mouse model imaging, electrophysiology, immunocytochemistry, behavioral assays, VPS26B depletion experiments","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, ICC, behavior) with loss-of-function, single lab","pmids":["34965419"],"is_preprint":false},{"year":2020,"finding":"Acute retromer inactivation (knocksideways technology applied to VPS26A/VPS26B-containing retromer) in HeLa and H4 cells causes time-resolved defects in cell surface sorting of GLUT1, but no quantifiable defect in CI-MPR sorting was detected, suggesting retromer has a comparatively limited role in ESCPE-1-mediated CI-MPR retrograde sorting.","method":"Knocksideways acute inactivation technology, quantitative trafficking assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acute inactivation with time-resolved readouts, two cell lines; negative result for CI-MPR reported explicitly","pmids":["32747499"],"is_preprint":false},{"year":2022,"finding":"Depletion of VPS26 (VPS26A or VPS26B) in mammalian cells leads to decreased primary ciliogenesis. Retromer co-immunoprecipitates with the centriolar protein CP110 and is required for CP110 removal from the mother centriole, defining a novel role for retromer in ciliogenesis.","method":"CRISPR/Cas9 knockout (C. elegans model), siRNA depletion in mammalian cells, co-immunoprecipitation, immunofluorescence ciliogenesis assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP and loss-of-function with defined ciliogenesis phenotype; VPS26A/B not distinguished individually","pmids":["35510502"],"is_preprint":false},{"year":2024,"finding":"VPS26B forms a trimeric complex with SHIP164 and the ATPase RhoBTB3 at Golgi-early endosome contacts, acting as a novel Rab14 effector. This complex promotes early endosome bud formation through a lipid transfer-dependent mechanism; Rab14 activity regulates SHIP164 association with endosomes, and depletion of VPS26B phenocopies SHIP164 depletion (enlarged Rab14+ EEs without buds).","method":"Co-immunoprecipitation, protein complex identification, depletion/knockdown with phenotypic rescue, live imaging, lipid transfer-defective mutant analysis","journal":"Cell discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — complex identification by co-IP, loss-of-function with specific endosomal morphology phenotype, rescue with wild-type but not lipid transfer-defective mutants, novel effector relationship established","pmids":["38565878"],"is_preprint":false}],"current_model":"VPS26B is a retromer subunit that forms an alternative Vps26B-Vps29-Vps35 trimeric complex (distinct from Vps26A-retromer) by binding Vps35 via a conserved C-terminal surface patch; it mediates endosomal recycling of specific cargo (including GLUT1, PAR-2, sortilin, glutamate receptors, and SORL1) but not CI-M6PR (whose sorting is controlled by the Vps26B C-terminal variable region), acts as a Rab14 effector in a RhoBTB3-SHIP164-Vps26B complex that drives early endosome bud formation at Golgi-EE contacts, is phosphorylated by NEK1 to regulate endosomal trafficking, and is recruited by viral proteins (e.g., MCMV M45) to facilitate aggrephagy-based immune evasion."},"narrative":{"mechanistic_narrative":"VPS26B is a paralog-specific subunit of the retromer complex that assembles into an alternative Vps26B-Vps29-Vps35 trimer and directs endosomal recycling of a distinct cargo repertoire [PMID:18088321, PMID:18656452]. Structurally related to the arrestin family, VPS26B is incorporated into retromer through binding of Vps35 to a conserved C-terminal surface patch, an interaction required for its endosomal recruitment; VPS26B and VPS26A bind Vps35/Vps29 with nanomolar affinity and compete for a single site, defining mutually exclusive retromer complexes [PMID:18088321]. VPS26B is essential for stability of the Vps26B-containing complex, as its loss severely reduces Vps35 while leaving the Vps26A complex intact [PMID:21040701]. The two paralogous complexes diverge in cargo selection: VPS26B-retromer fails to sort CI-M6PR—a specificity governed by the VPS26B C-terminal variable region—instead routing the receptor to degradation, while supporting recycling of sortilin, GLUT1, the GPCR PAR-2, and neuronal glutamate receptors and SORL1 [PMID:21920005, PMID:21040701, PMID:26113136, PMID:34965419, PMID:32747499]. Beyond canonical retromer recycling, VPS26B serves as a Rab14 effector within a RhoBTB3-SHIP164-VPS26B complex that drives lipid-transfer-dependent early endosome bud formation at Golgi-early endosome contacts [PMID:38565878], is phosphorylated by NEK1 to regulate endosomal trafficking [PMID:34376696], and is recruited together with TBC1D5 by murine cytomegalovirus M45 to support aggrephagy-mediated immune evasion [PMID:31844296].","teleology":[{"year":2005,"claim":"Established whether VPS26B is a bona fide retromer component, answering whether the VPS26A paralog has a functional counterpart in the complex.","evidence":"Co-IP, yeast two-hybrid, fractionation and fluorescence imaging in HeLa/A549/HEK293 cells","pmids":["16190980"],"confidence":"Medium","gaps":["Distinct localization from VPS26A described but cargo and functional role not defined","Direct binding interface with Vps35 not mapped"]},{"year":2007,"claim":"Defined the structural basis of VPS26B incorporation into retromer and showed the two paralogs form separate, competing complexes, framing the question of why two paralogous retromers exist.","evidence":"X-ray crystallography of mouse Vps26B with structure-based mutagenesis, quantitative in vitro binding and competition assays, in vivo co-IP","pmids":["18088321"],"confidence":"High","gaps":["Functional consequence of distinct complexes not established","Cargo specificity differences not yet identified"]},{"year":2008,"claim":"Confirmed tissue-specific assembly of a discrete Vps26b retromer distinct from Vps26a/Vps26aT complexes, extending the paralog-specific model in vivo.","evidence":"Immunoprecipitation, pull-down, Western blot and RT-PCR in mouse testis","pmids":["18656452"],"confidence":"Medium","gaps":["No cargo or trafficking function assigned in testis context"]},{"year":2010,"claim":"Showed VPS26B is required for stability of its own retromer complex and identified sortilin as a transport cargo, linking the paralog to specific endosome-to-TGN sorting.","evidence":"Vps26b knockout mice with Western blot and protein-level quantification","pmids":["21040701"],"confidence":"Medium","gaps":["Mechanism of sortilin handover not resolved","Single lab; broader cargo set not surveyed"]},{"year":2011,"claim":"Resolved why the two paralogous retromers differ functionally by mapping cargo discrimination to the VPS26B C-terminal variable region, which excludes CI-M6PR.","evidence":"Reciprocal co-IP, deletion mutagenesis with rescue, and receptor/secretion trafficking assays in stable HEK293 lines","pmids":["21920005"],"confidence":"High","gaps":["Structural basis of variable-region cargo exclusion not defined","Full cargo set distinguishing the paralogs incomplete"]},{"year":2015,"claim":"Demonstrated a physiological consequence of VPS26B recycling by showing it controls plasma membrane resensitization of the GPCR PAR-2.","evidence":"Calcium release, ERK1/2 signaling, and receptor resensitization assays in VPS26B-overexpressing HEK293 cells","pmids":["26113136"],"confidence":"Medium","gaps":["Effect shown by overexpression; loss-of-function consequence not tested","Direct VPS26B-PAR-2 engagement not demonstrated"]},{"year":2019,"claim":"Identified a non-canonical role for VPS26B as part of the aggrephagy machinery, co-opted by a viral protein for immune evasion.","evidence":"Co-IP, protein aggregation and degradation assays, and M45 motif mutagenesis (MCMV system)","pmids":["31844296"],"confidence":"Medium","gaps":["Endogenous (non-viral) aggrephagy role of VPS26B not established","How VPS26B/TBC1D5 link aggregates to LC3 mechanistically unclear"]},{"year":2020,"claim":"Used acute inactivation to define the cargo dependence of retromer, confirming GLUT1 requires retromer while CI-MPR sorting is comparatively retromer-independent.","evidence":"Knocksideways acute retromer inactivation with time-resolved quantitative trafficking assays in HeLa and H4 cells","pmids":["32747499"],"confidence":"Medium","gaps":["VPS26A and VPS26B contributions not separated in this assay","Paralog-specific cargo not individually resolved"]},{"year":2021,"claim":"Placed VPS26B downstream of a kinase by showing NEK1 directly phosphorylates it to regulate endosomal trafficking, linking retromer to NEK1-RIPK1 pathway biology.","evidence":"In vitro kinase assay on VPS26B plus genetic epistasis (NEK1 KO rescued by RIPK1 inactivation) and trafficking assays in mice","pmids":["34376696"],"confidence":"Medium","gaps":["Phosphosite(s) on VPS26B and their functional consequence not mapped","Direct link between phosphorylation and specific cargo not established"]},{"year":2021,"claim":"Established a dedicated neuronal function for VPS26B-organized retromer in recycling glutamate receptors and SORL1, connecting it to synaptic integrity.","evidence":"Mouse imaging, electrophysiology, immunocytochemistry, behavior, and VPS26B depletion","pmids":["34965419"],"confidence":"Medium","gaps":["Direct cargo engagement vs. indirect effect not dissected","Molecular determinants of neuronal cargo selectivity unknown"]},{"year":2024,"claim":"Revealed a retromer-independent function in which VPS26B acts as a Rab14 effector driving early endosome bud formation through lipid transfer at Golgi-EE contacts.","evidence":"Co-IP complex identification, depletion with phenotypic rescue, live imaging, and lipid-transfer-defective mutant analysis","pmids":["38565878"],"confidence":"High","gaps":["How VPS26B partitions between classic retromer and the RhoBTB3-SHIP164 complex unknown","Structural basis of VPS26B-SHIP164-RhoBTB3 assembly not determined"]},{"year":null,"claim":"How VPS26B's phosphorylation, paralog-specific cargo selection, and distribution among its multiple complexes (retromer, RhoBTB3-SHIP164, aggrephagy) are coordinated in a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified regulatory model integrating NEK1 phosphorylation with complex choice","Structural definition of VPS26B in non-retromer complexes lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,4,9,10]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6]}],"complexes":["retromer (Vps26B-Vps29-Vps35)","RhoBTB3-SHIP164-VPS26B complex"],"partners":["VPS35","VPS29","TBC1D5","GOLPH3","SHIP164","RHOBTB3","NEK1","CP110"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q4G0F5","full_name":"Vacuolar protein sorting-associated protein 26B","aliases":["Vesicle protein sorting 26B"],"length_aa":336,"mass_kda":39.2,"function":"Acts as a component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. The recruitment of the CSC to the endosomal membrane involves RAB7A and SNX3. 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 SNX3-retromer mediates the retrograde transport of WLS distinct from the SNX-BAR retromer pathway. The SNX27-retromer is believed to be involved in endosome-to-plasma membrane trafficking and recycling of a broad spectrum of cargo proteins. The CSC seems to act as recruitment hub for other proteins, such as the WASH complex and TBC1D5. May be involved in retrograde transport of SORT1 but not of IGF2R. Acts redundantly with VSP26A in SNX-27 mediated endocytic recycling of SLC2A1/GLUT1 (By similarity)","subcellular_location":"Cytoplasm; Membrane; Early endosome; Late endosome","url":"https://www.uniprot.org/uniprotkb/Q4G0F5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VPS26B","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"VPS35","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/VPS26B","total_profiled":1310},"omim":[{"mim_id":"610027","title":"VPS26 RETROMER COMPLEX COMPONENT B; VPS26B","url":"https://www.omim.org/entry/610027"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/VPS26B"},"hgnc":{"alias_symbol":["MGC10485","Pep8b"],"prev_symbol":[]},"alphafold":{"accession":"Q4G0F5","domains":[{"cath_id":"2.60.40.640","chopping":"9-148","consensus_level":"high","plddt":95.9483,"start":9,"end":148},{"cath_id":"2.60.40.640","chopping":"161-292","consensus_level":"high","plddt":93.4893,"start":161,"end":292}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4G0F5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q4G0F5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q4G0F5-F1-predicted_aligned_error_v6.png","plddt_mean":86.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VPS26B","jax_strain_url":"https://www.jax.org/strain/search?query=VPS26B"},"sequence":{"accession":"Q4G0F5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q4G0F5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q4G0F5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4G0F5"}},"corpus_meta":[{"pmid":"18088321","id":"PMC_18088321","title":"Structure of Vps26B and mapping of its interaction with the retromer protein complex.","date":"2007","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/18088321","citation_count":99,"is_preprint":false},{"pmid":"21920005","id":"PMC_21920005","title":"Vps26A and Vps26B subunits define distinct retromer complexes.","date":"2011","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/21920005","citation_count":87,"is_preprint":false},{"pmid":"16190980","id":"PMC_16190980","title":"A novel mammalian retromer component, Vps26B.","date":"2005","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/16190980","citation_count":78,"is_preprint":false},{"pmid":"31844296","id":"PMC_31844296","title":"Herpesviruses induce aggregation and selective autophagy of host signalling proteins NEMO and RIPK1 as an immune-evasion mechanism.","date":"2019","source":"Nature 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microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39944650","citation_count":7,"is_preprint":false},{"pmid":"38565878","id":"PMC_38565878","title":"Biogenesis of Rab14-positive endosome buds at Golgi-endosome contacts by the RhoBTB3-SHIP164-Vps26B complex.","date":"2024","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/38565878","citation_count":5,"is_preprint":false},{"pmid":"21359680","id":"PMC_21359680","title":"Quantitative analysis of retromer complex-related genes during embryo development in the mouse.","date":"2011","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/21359680","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11829,"output_tokens":3384,"usd":0.043124,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10883,"output_tokens":3617,"usd":0.07242,"stage2_stop_reason":"end_turn"},"total_usd":0.115544,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of mouse Vps26B was determined, revealing a striking structural similarity to the arrestin family of proteins. Structure-based mutagenesis showed that both Vps26A and Vps26B are incorporated into retromer complexes through binding of Vps35 to a highly conserved surface patch within the C-terminal subdomain, and this interaction is required for endosomal recruitment of the proteins.\",\n      \"method\": \"X-ray crystallography, structure-based mutagenesis, biochemical binding assays\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional validation of endosomal recruitment\",\n      \"pmids\": [\"18088321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Both Vps26A and Vps26B bind to Vps35/Vps29 with nanomolar affinity and compete for a single binding site, defining distinct retromer complexes in vitro and in vivo.\",\n      \"method\": \"In vitro binding assays (affinity measurements), competition assays, co-immunoprecipitation\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — quantitative in vitro binding and in vivo co-IP in same study, replicated by subsequent papers\",\n      \"pmids\": [\"18088321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Vps26B is a peripheral membrane protein that co-precipitates with Vps35 from transfected cells; direct interaction was confirmed by yeast two-hybrid analysis, establishing Vps26B as a subunit of the retromer complex. In HeLa cells, Vps26B localizes to cytoplasm with low levels at the plasma membrane (distinct from Vps26A which is predominantly endosomal). In A549 cells, Vps26B co-localizes with actin-rich lamellipodia. TIRF microscopy confirmed plasma membrane association of CFP-Vps26B in HEK293 cells.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, subcellular fractionation, fluorescence microscopy, TIRF microscopy\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple orthogonal methods (Co-IP, Y2H, live imaging) in single lab establishing protein-protein interaction and distinct localization\",\n      \"pmids\": [\"16190980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Vps26B-retromer associates with TBC1D5 and GOLPH3 (like Vps26A-retromer), but unlike Vps26A-retromer, Vps26B-retromer does not interact with CI-M6PR, leading to degradation of this receptor and increased cathepsin D secretion. Deletion of the variable Vps26B C-terminal region restores CI-M6PR cycling, indicating that this region directly controls differential cargo selection between the two paralogous retromer complexes.\",\n      \"method\": \"Co-immunoprecipitation, stable cell lines (HEK293 expressing Vps26A-myc or Vps26B-myc), deletion mutagenesis, receptor trafficking assays, secretion assays\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, deletion mutagenesis with rescue, functional cargo-sorting readouts; replicated finding from same group with orthogonal methods\",\n      \"pmids\": [\"21920005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Vps26b knockout mice lack the Vps26b-Vps29-Vps35 retromer complex and show a severe reduction of Vps35 protein, while the Vps26a-Vps29-Vps35 complex remains intact. Sortilin protein levels are increased approximately 20% in Vps26b-deficient mice, implicating Vps26b-Vps29-Vps35 retromer in sortilin transport from endosomes to the TGN.\",\n      \"method\": \"Vps26b knockout mice, Western blot, co-immunoprecipitation, protein level quantification\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with specific molecular and cargo phenotype, single lab\",\n      \"pmids\": [\"21040701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In mouse testis, Vps26b forms a Vps26b-Vps29-Vps35 retromer complex that is distinct from the Vps26a-Vps29-Vps35 and Vps26aT-Vps29-Vps35 complexes; direct interaction of Vps26b with Vps35 was demonstrated by immunoprecipitation and pull-down assay.\",\n      \"method\": \"Immunoprecipitation, pull-down assay, Western blot, RT-PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and pull-down, replicated interaction finding from prior studies in a tissue-specific context\",\n      \"pmids\": [\"18656452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Murine cytomegalovirus M45 protein recruits VPS26B and the LC3-interacting adaptor protein TBC1D5 to facilitate degradation of NEMO and RIPK1 protein aggregates by selective autophagy (aggrephagy), revealing VPS26B as a component of the aggrephagy machinery exploited for viral immune evasion.\",\n      \"method\": \"Co-immunoprecipitation, protein aggregation assays, autophagy/degradation assays, mutagenesis of M45 aggregation motif\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and functional degradation assays in single study; VPS26B role defined mechanistically within aggrephagy pathway\",\n      \"pmids\": [\"31844296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NEK1 kinase regulates retromer-mediated endosomal trafficking by directly phosphorylating VPS26B. NEK1 deficiency disrupts endosomal trafficking of plasma membrane proteins, and genetic inactivation of RIPK1 can rescue postnatal lethality and blood-brain barrier damage in NEK1-deficient mice.\",\n      \"method\": \"Kinase assay (phosphorylation of VPS26B by NEK1), genetic epistasis (NEK1 KO with RIPK1 inactivation rescue), endosomal trafficking assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation demonstrated and genetic rescue confirms pathway position, single lab study\",\n      \"pmids\": [\"34376696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Vps26B-retromer negatively regulates plasma membrane resensitization of PAR-2 (a protease-activated G protein-coupled receptor). Overexpression of Vps26B causes a significant delay in plasma membrane repopulation of PAR-2 following receptor stimulation, resulting in impaired PAR-2 activation after resensitization, without affecting initial receptor activation, ERK1/2 signaling, or endocytosis.\",\n      \"method\": \"Stable HEK293 cell line expressing Vps26B, calcium release assays, ERK1/2 signaling assays, receptor trafficking/resensitization assays\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional receptor trafficking assays with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"26113136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Neurons are enriched with a VPS26B-organized retromer core that is differentially dedicated to endosomal recycling. VPS26B regulates glutamate receptor and SORL1 recycling, and its depletion causes synaptic dysfunction particularly in the trans-entorhinal cortex.\",\n      \"method\": \"Mouse model imaging, electrophysiology, immunocytochemistry, behavioral assays, VPS26B depletion experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (electrophysiology, ICC, behavior) with loss-of-function, single lab\",\n      \"pmids\": [\"34965419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Acute retromer inactivation (knocksideways technology applied to VPS26A/VPS26B-containing retromer) in HeLa and H4 cells causes time-resolved defects in cell surface sorting of GLUT1, but no quantifiable defect in CI-MPR sorting was detected, suggesting retromer has a comparatively limited role in ESCPE-1-mediated CI-MPR retrograde sorting.\",\n      \"method\": \"Knocksideways acute inactivation technology, quantitative trafficking assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acute inactivation with time-resolved readouts, two cell lines; negative result for CI-MPR reported explicitly\",\n      \"pmids\": [\"32747499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Depletion of VPS26 (VPS26A or VPS26B) in mammalian cells leads to decreased primary ciliogenesis. Retromer co-immunoprecipitates with the centriolar protein CP110 and is required for CP110 removal from the mother centriole, defining a novel role for retromer in ciliogenesis.\",\n      \"method\": \"CRISPR/Cas9 knockout (C. elegans model), siRNA depletion in mammalian cells, co-immunoprecipitation, immunofluorescence ciliogenesis assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP and loss-of-function with defined ciliogenesis phenotype; VPS26A/B not distinguished individually\",\n      \"pmids\": [\"35510502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VPS26B forms a trimeric complex with SHIP164 and the ATPase RhoBTB3 at Golgi-early endosome contacts, acting as a novel Rab14 effector. This complex promotes early endosome bud formation through a lipid transfer-dependent mechanism; Rab14 activity regulates SHIP164 association with endosomes, and depletion of VPS26B phenocopies SHIP164 depletion (enlarged Rab14+ EEs without buds).\",\n      \"method\": \"Co-immunoprecipitation, protein complex identification, depletion/knockdown with phenotypic rescue, live imaging, lipid transfer-defective mutant analysis\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complex identification by co-IP, loss-of-function with specific endosomal morphology phenotype, rescue with wild-type but not lipid transfer-defective mutants, novel effector relationship established\",\n      \"pmids\": [\"38565878\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VPS26B is a retromer subunit that forms an alternative Vps26B-Vps29-Vps35 trimeric complex (distinct from Vps26A-retromer) by binding Vps35 via a conserved C-terminal surface patch; it mediates endosomal recycling of specific cargo (including GLUT1, PAR-2, sortilin, glutamate receptors, and SORL1) but not CI-M6PR (whose sorting is controlled by the Vps26B C-terminal variable region), acts as a Rab14 effector in a RhoBTB3-SHIP164-Vps26B complex that drives early endosome bud formation at Golgi-EE contacts, is phosphorylated by NEK1 to regulate endosomal trafficking, and is recruited by viral proteins (e.g., MCMV M45) to facilitate aggrephagy-based immune evasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VPS26B is a paralog-specific subunit of the retromer complex that assembles into an alternative Vps26B-Vps29-Vps35 trimer and directs endosomal recycling of a distinct cargo repertoire [#1, #5]. Structurally related to the arrestin family, VPS26B is incorporated into retromer through binding of Vps35 to a conserved C-terminal surface patch, an interaction required for its endosomal recruitment; VPS26B and VPS26A bind Vps35/Vps29 with nanomolar affinity and compete for a single site, defining mutually exclusive retromer complexes [#0, #1]. VPS26B is essential for stability of the Vps26B-containing complex, as its loss severely reduces Vps35 while leaving the Vps26A complex intact [#4]. The two paralogous complexes diverge in cargo selection: VPS26B-retromer fails to sort CI-M6PR—a specificity governed by the VPS26B C-terminal variable region—instead routing the receptor to degradation, while supporting recycling of sortilin, GLUT1, the GPCR PAR-2, and neuronal glutamate receptors and SORL1 [#3, #4, #8, #9, #10]. Beyond canonical retromer recycling, VPS26B serves as a Rab14 effector within a RhoBTB3-SHIP164-VPS26B complex that drives lipid-transfer-dependent early endosome bud formation at Golgi-early endosome contacts [#12], is phosphorylated by NEK1 to regulate endosomal trafficking [#7], and is recruited together with TBC1D5 by murine cytomegalovirus M45 to support aggrephagy-mediated immune evasion [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established whether VPS26B is a bona fide retromer component, answering whether the VPS26A paralog has a functional counterpart in the complex.\",\n      \"evidence\": \"Co-IP, yeast two-hybrid, fractionation and fluorescence imaging in HeLa/A549/HEK293 cells\",\n      \"pmids\": [\"16190980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Distinct localization from VPS26A described but cargo and functional role not defined\", \"Direct binding interface with Vps35 not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the structural basis of VPS26B incorporation into retromer and showed the two paralogs form separate, competing complexes, framing the question of why two paralogous retromers exist.\",\n      \"evidence\": \"X-ray crystallography of mouse Vps26B with structure-based mutagenesis, quantitative in vitro binding and competition assays, in vivo co-IP\",\n      \"pmids\": [\"18088321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of distinct complexes not established\", \"Cargo specificity differences not yet identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Confirmed tissue-specific assembly of a discrete Vps26b retromer distinct from Vps26a/Vps26aT complexes, extending the paralog-specific model in vivo.\",\n      \"evidence\": \"Immunoprecipitation, pull-down, Western blot and RT-PCR in mouse testis\",\n      \"pmids\": [\"18656452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cargo or trafficking function assigned in testis context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed VPS26B is required for stability of its own retromer complex and identified sortilin as a transport cargo, linking the paralog to specific endosome-to-TGN sorting.\",\n      \"evidence\": \"Vps26b knockout mice with Western blot and protein-level quantification\",\n      \"pmids\": [\"21040701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of sortilin handover not resolved\", \"Single lab; broader cargo set not surveyed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved why the two paralogous retromers differ functionally by mapping cargo discrimination to the VPS26B C-terminal variable region, which excludes CI-M6PR.\",\n      \"evidence\": \"Reciprocal co-IP, deletion mutagenesis with rescue, and receptor/secretion trafficking assays in stable HEK293 lines\",\n      \"pmids\": [\"21920005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of variable-region cargo exclusion not defined\", \"Full cargo set distinguishing the paralogs incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated a physiological consequence of VPS26B recycling by showing it controls plasma membrane resensitization of the GPCR PAR-2.\",\n      \"evidence\": \"Calcium release, ERK1/2 signaling, and receptor resensitization assays in VPS26B-overexpressing HEK293 cells\",\n      \"pmids\": [\"26113136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect shown by overexpression; loss-of-function consequence not tested\", \"Direct VPS26B-PAR-2 engagement not demonstrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a non-canonical role for VPS26B as part of the aggrephagy machinery, co-opted by a viral protein for immune evasion.\",\n      \"evidence\": \"Co-IP, protein aggregation and degradation assays, and M45 motif mutagenesis (MCMV system)\",\n      \"pmids\": [\"31844296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous (non-viral) aggrephagy role of VPS26B not established\", \"How VPS26B/TBC1D5 link aggregates to LC3 mechanistically unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Used acute inactivation to define the cargo dependence of retromer, confirming GLUT1 requires retromer while CI-MPR sorting is comparatively retromer-independent.\",\n      \"evidence\": \"Knocksideways acute retromer inactivation with time-resolved quantitative trafficking assays in HeLa and H4 cells\",\n      \"pmids\": [\"32747499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"VPS26A and VPS26B contributions not separated in this assay\", \"Paralog-specific cargo not individually resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed VPS26B downstream of a kinase by showing NEK1 directly phosphorylates it to regulate endosomal trafficking, linking retromer to NEK1-RIPK1 pathway biology.\",\n      \"evidence\": \"In vitro kinase assay on VPS26B plus genetic epistasis (NEK1 KO rescued by RIPK1 inactivation) and trafficking assays in mice\",\n      \"pmids\": [\"34376696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosite(s) on VPS26B and their functional consequence not mapped\", \"Direct link between phosphorylation and specific cargo not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a dedicated neuronal function for VPS26B-organized retromer in recycling glutamate receptors and SORL1, connecting it to synaptic integrity.\",\n      \"evidence\": \"Mouse imaging, electrophysiology, immunocytochemistry, behavior, and VPS26B depletion\",\n      \"pmids\": [\"34965419\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cargo engagement vs. indirect effect not dissected\", \"Molecular determinants of neuronal cargo selectivity unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a retromer-independent function in which VPS26B acts as a Rab14 effector driving early endosome bud formation through lipid transfer at Golgi-EE contacts.\",\n      \"evidence\": \"Co-IP complex identification, depletion with phenotypic rescue, live imaging, and lipid-transfer-defective mutant analysis\",\n      \"pmids\": [\"38565878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How VPS26B partitions between classic retromer and the RhoBTB3-SHIP164 complex unknown\", \"Structural basis of VPS26B-SHIP164-RhoBTB3 assembly not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How VPS26B's phosphorylation, paralog-specific cargo selection, and distribution among its multiple complexes (retromer, RhoBTB3-SHIP164, aggrephagy) are coordinated in a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified regulatory model integrating NEK1 phosphorylation with complex choice\", \"Structural definition of VPS26B in non-retromer complexes lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 4, 9, 10]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"retromer (Vps26B-Vps29-Vps35)\", \"RhoBTB3-SHIP164-VPS26B complex\"],\n    \"partners\": [\"VPS35\", \"VPS29\", \"TBC1D5\", \"GOLPH3\", \"SHIP164\", \"RhoBTB3\", \"NEK1\", \"CP110\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}