{"gene":"M6PR","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2004,"finding":"GGA1 binds to the CD-MPR cytoplasmic tail via the DXXLL motif (residues 61-65), with acidic residues Glu58 and Glu59 required for high-affinity binding in vitro; phosphorylation of Ser57 by CK2 has no influence on GGA1 or AP-1 binding. AP-1 binding requires Glu55, Glu56, Glu58, and Glu59 but is also independent of Ser57 phosphorylation. GGA1 binds with ~2.4-fold higher affinity than AP-1 to overlapping sorting signals on CD-MPR.","method":"In vitro binding assays with site-directed mutagenesis of CD-MPR cytoplasmic tail residues; in vivo co-immunoprecipitation of GGA1/AP-1 with CD-MPR mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding reconstitution with systematic mutagenesis plus in vivo co-IP validation, single lab but multiple orthogonal methods","pmids":["15044437"],"is_preprint":false},{"year":1990,"finding":"The 46 kDa M6PR (CD-MPR) cycles between the Golgi complex (concentrated in middle/trans cisternae at steady state) and late endosomes (multivesicular endosomes), following the same intracellular itinerary as the 215 kDa CI-M6PR; both receptors co-localize in the same population of late endosomes after weak base treatment.","method":"Immunofluorescence and immunoperoxidase labeling with antipeptide antibodies to the C-terminal cytoplasmic domain; chloroquine/NH4Cl treatments; double-labeling for both M6PRs","journal":"European journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct subcellular fractionation/localization with multiple cell types and pharmacological perturbation, replicated across cell lines","pmids":["1964415"],"is_preprint":false},{"year":2012,"finding":"CD-M6PR (chimeric CD8-M6PR) retrograde trafficking from early endosomes to the Golgi requires transit through the recycling endosome; retromer is required for exit from early endosomes (ablation leaves cargo in EE), whereas EHD1 is not significantly required for CD8-M6PR trafficking from recycling endosome to TGN.","method":"Knockdown of retromer components and ablation of recycling endosomes; confocal immunofluorescence tracking of chimeric CD8-CI-M6PR cargo in HeLa cells","journal":"Traffic (Copenhagen, Denmark)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined compartmental phenotype readout, single lab, two orthogonal perturbations","pmids":["22540229"],"is_preprint":false},{"year":2020,"finding":"M6PR shuttling mediated by GCC2 facilitates release of phosphorothioate antisense oligonucleotides (PS-ASOs) from late endosomes; M6PR co-localizes with PS-ASOs in late endosomes and binds PS-ASOs, and reduction of M6PR impairs PS-ASO endosomal escape and activity in human and mouse cells in vivo.","method":"siRNA knockdown of M6PR and GCC2; co-localization immunofluorescence; in vivo mouse subcutaneous PS-ASO treatment; functional ASO activity assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with functional readout, co-localization, and in vivo confirmation; single lab but multiple orthogonal methods","pmids":["31840180"],"is_preprint":false},{"year":2022,"finding":"RUFY1, recruited to endosomes via Arl8b-regulated interaction with Rab14, mediates CI-M6PR retrieval from endosomes to the TGN via dynein-dynactin; RUFY1 depletion delays CI-M6PR endosome-to-TGN retrieval and impairs delivery of newly synthesized hydrolases to lysosomes.","method":"Co-IP, siRNA depletion, dominant-negative and reconstitution experiments; co-localization with endosomal markers; dynein-dynactin interaction mapping","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, siRNA KD, reconstitution of RUFY1, multiple markers; single lab but multiple orthogonal methods","pmids":["36282215"],"is_preprint":false},{"year":2023,"finding":"CLN3 interacts with CI-M6PR (cation-independent M6PR) and is required for its correct trafficking; CLN3 depletion causes mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation, while CLN3 overexpression promotes CI-M6PR-dependent lysosomal tubulation and proto-lysosome formation.","method":"Proteomic/co-IP interaction analysis; siRNA knockdown and overexpression of CLN3; lysosomal enzyme sorting assays; live imaging of lysosomal tubules","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP/proteomics, loss- and gain-of-function with multiple phenotypic readouts, single lab but orthogonal methods","pmids":["37400440"],"is_preprint":false},{"year":2022,"finding":"CD-M6PR is present in mature late endosomes containing hSCARB2, RAB9, BMP, and LAMP2; siRNA knockdown of CD-M6PR impairs EV71 productive uncoating, placing CD-M6PR as a required host factor for EV71 uncoating in late endosomes.","method":"siRNA knockdown of CD-M6PR; immunofluorescence co-localization of M6PR with endosomal markers; viral growth/entry assays in hSCARB2-overexpressing cells","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA KD with viral functional readout and localization data, single lab, single study","pmids":["35929543"],"is_preprint":false},{"year":2023,"finding":"M6PR interacts with the ectodomain of the influenza A virus HA2 subunit via its lumenal domain; this interaction directly promotes fusion of the viral envelope with late endosomal membranes. siRNA knockdown of M6PR inhibited IAV replication by blocking membrane fusion without affecting viral attachment, internalization, early endosome trafficking, or late endosome acidification.","method":"siRNA knockdown; co-immunoprecipitation of M6PR with HA; domain-mapping experiments; viral entry step-specific assays; NP nuclear accumulation assays","journal":"Science China. Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP domain mapping, siRNA KD, stepwise entry dissection; single lab, multiple orthogonal methods","pmids":["38038885"],"is_preprint":false},{"year":2022,"finding":"RAB31 downregulation (downstream of RUNX1 haplodeficiency) impairs trafficking of M6PR at the level of early endosomes in megakaryocytes, resulting in enlarged early endosomes; reconstitution of RAB31 partially reverses this endosomal defect.","method":"siRNA and CRISPR/Cas9 knockdown of RUNX1 and RAB31; immunofluorescence for EEA1/CD63; patient-derived iPSC-megakaryocytes; RAB31 reconstitution","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD, patient-derived model, reconstitution rescue, multiple markers; single lab","pmids":["35839075"],"is_preprint":false},{"year":2019,"finding":"GCC88 (trans-Golgi golgin tethering factor) is required for endosome-to-TGN retrograde transport of CI-M6PR; GCC88 knockout reduces cellular CI-M6PR levels, impairs cathepsin-D processing (a CI-M6PR-dependent lysosomal hydrolase), and reduces lysosomal proteolytic capacity.","method":"GCC88 knockout cells; immunofluorescence and western blot of CI-M6PR; cathepsin-D maturation assay; lysosomal protease activity assay","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KO with defined functional readout, single lab, single study","pmids":["30791178"],"is_preprint":false},{"year":2026,"finding":"In senescent cells, CD-M6PR undergoes accelerated proteasome-mediated degradation driven by the E3 ubiquitin ligase ZNRF2 (whose expression is elevated via mTORC1 activation under stress); this ZNRF2-mediated CD-M6PR reduction impairs lysosomal enzyme trafficking and autolysosomal function, exacerbating senescence via a mTORC1-ZNRF2-CD-M6PR axis.","method":"Structural prediction and experimental validation; immunoprecipitation; Western blot; proteasome inhibitor experiments; ZNRF2 knockdown/overexpression; mTORC1 inhibition","journal":"GeroScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, pharmacological and genetic perturbation, structural prediction with experimental validation; single lab, multiple orthogonal methods","pmids":["42065825"],"is_preprint":false},{"year":2025,"finding":"Berberine upregulates M6PR specifically in senescent cells; upregulated M6PR binds STING and sorts it into endosomes for degradation, suppressing STING signaling and senescence-associated secretory phenotypes. M6PR knockdown abrogates berberine's anti-senescence effects even when STING expression is reversed.","method":"Immunoprecipitation of M6PR-STING; immunofluorescence for endosomal co-localization; cell thermal shift assay; M6PR siRNA knockdown rescue experiments; Western blot for STING/IFN-β","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, cellular thermal shift, KD rescue; single lab, multiple orthogonal methods","pmids":["40714423"],"is_preprint":false},{"year":2018,"finding":"The luminal/extracellular domain of CI-M6PR influences its TGN targeting: partial deletion or replacement of the luminal domain misdirects the receptor to non-TGN compartments, while a short HA-tagged C-terminal tail construct (HA-hCI-M6PR-tail) traffics preferentially to TGN. The retromer complex regulates trafficking of the luminal-truncated form through interaction with SNX5.","method":"Deletion and chimeric domain-swap mutants of CI-M6PR; immunofluorescence localization in transfected cells; co-immunoprecipitation with retromer/SNX5","journal":"Journal of biomedical research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — domain-swap mutagenesis with localization readout and Co-IP; single lab, single study","pmids":["29988026"],"is_preprint":false}],"current_model":"CD-MPR (M6PR) cycles between the trans-Golgi network and late endosomes to deliver mannose-6-phosphate-tagged lysosomal enzymes; its cytoplasmic tail contains overlapping sorting signals (DXXLL motif, acidic cluster) that recruit GGA1 (higher affinity) and AP-1 for TGN-to-endosome transport, while retromer (via SNX5/RUFY1-dynein) and golgins (GCC88, GCC2) mediate retrograde endosome-to-TGN retrieval through the recycling endosome; its stability is controlled by the E3 ligase ZNRF2 (elevated by mTORC1 in senescence) that targets it for proteasomal degradation; beyond lysosomal biogenesis, M6PR also facilitates endosomal escape of antisense oligonucleotides, promotes viral membrane fusion (IAV HA2 interaction), and mediates STING endosomal sorting for degradation."},"narrative":{"mechanistic_narrative":"M6PR (CD-MPR) is a cargo receptor that cycles between the trans-Golgi network and late endosomes to deliver mannose-6-phosphate-tagged lysosomal enzymes, following an itinerary shared with the larger cation-independent receptor [PMID:1964415]. Anterograde TGN-to-endosome sorting is directed by overlapping signals in its cytoplasmic tail: a DXXLL motif (residues 61-65) flanked by acidic residues recruits GGA1 with higher affinity than AP-1, with both interactions independent of CK2-mediated Ser57 phosphorylation [PMID:15044437]. Retrograde retrieval from endosomes to the TGN proceeds through the recycling endosome and depends on retromer for early-endosome exit [PMID:22540229], with RUFY1 (recruited via Arl8b/Rab14) coupling cargo to dynein-dynactin [PMID:36282215] and golgin tethers GCC88 and GCC2 completing TGN delivery [PMID:30791178, PMID:31840180]; loss of these factors reduces receptor levels, impairs cathepsin-D processing, and lowers lysosomal proteolytic capacity [PMID:30791178]. Receptor abundance is further controlled by accelerated proteasomal degradation via the E3 ligase ZNRF2 in senescent cells, impairing lysosomal enzyme trafficking and autolysosomal function [PMID:42065825]. Beyond lysosomal biogenesis, M6PR's luminal domain promotes influenza A virus envelope fusion with late-endosomal membranes through interaction with the HA2 ectodomain [PMID:38038885], facilitates endosomal escape of phosphorothioate antisense oligonucleotides [PMID:31840180], and binds STING to sort it into endosomes for degradation, suppressing STING signaling [PMID:40714423].","teleology":[{"year":1990,"claim":"Establishing where the 46 kDa receptor resides answered whether it shares a trafficking route with the larger M6PR, defining its itinerary between Golgi and late endosomes.","evidence":"Immunofluorescence/immunoperoxidase with anti-cytoplasmic-tail antibodies and base treatment across cell types","pmids":["1964415"],"confidence":"High","gaps":["Did not resolve the molecular machinery directing each transport step","Steady-state localization does not establish kinetics of cycling"]},{"year":2004,"claim":"Mapping the cytoplasmic-tail sorting signals answered how adaptors are recruited for anterograde transport, showing GGA1 and AP-1 bind overlapping acidic/DXXLL signals with distinct affinities and independent of Ser57 phosphorylation.","evidence":"In vitro binding with site-directed mutagenesis plus in vivo co-IP of GGA1/AP-1 with CD-MPR mutants","pmids":["15044437"],"confidence":"High","gaps":["Functional consequence of differential GGA1 vs AP-1 affinity for cargo flux not quantified","Role of Ser57 phosphorylation, if any, left unresolved"]},{"year":2012,"claim":"Dissecting retrograde transport answered which compartments and factors are required, placing retromer at early-endosome exit and the recycling endosome as an obligatory waystation.","evidence":"siRNA knockdown of retromer and recycling-endosome ablation with confocal tracking of chimeric CD8-M6PR in HeLa","pmids":["22540229"],"confidence":"Medium","gaps":["Used a chimeric reporter rather than endogenous receptor","Single cell line; EHD1-independence not mechanistically explained"]},{"year":2018,"claim":"Testing the luminal domain answered whether TGN targeting information lies outside the cytoplasmic tail, showing the luminal domain influences correct targeting and links retromer regulation to SNX5.","evidence":"Domain-deletion/chimera mutants with localization imaging and co-IP with retromer/SNX5","pmids":["29988026"],"confidence":"Medium","gaps":["Mechanism by which the luminal domain dictates sorting unknown","Single study, overexpressed constructs"]},{"year":2019,"claim":"Knocking out the golgin GCC88 answered whether trans-Golgi tethering is required for retrieval, linking receptor recycling to lysosomal hydrolase maturation and proteolytic capacity.","evidence":"GCC88 knockout cells with CI-M6PR western/IF, cathepsin-D maturation and lysosomal protease assays","pmids":["30791178"],"confidence":"Medium","gaps":["Direct GCC88–M6PR contact not demonstrated","Single study"]},{"year":2022,"claim":"Identifying RUFY1 answered how endosome-to-TGN cargo is coupled to a motor, showing Arl8b/Rab14-recruited RUFY1 links the receptor to dynein-dynactin for retrieval and hydrolase delivery.","evidence":"Reciprocal Co-IP, siRNA depletion, dominant-negative and reconstitution with endosomal markers","pmids":["36282215"],"confidence":"High","gaps":["Direct vs indirect RUFY1–M6PR association not fully resolved","Studied for CI-M6PR; applicability to CD-M6PR not established"]},{"year":2022,"claim":"Linking RAB31 to receptor trafficking answered a disease-relevant question, showing RAB31 loss downstream of RUNX1 haplodeficiency disrupts M6PR transit at early endosomes in megakaryocytes.","evidence":"siRNA/CRISPR knockdown of RUNX1 and RAB31, patient iPSC-megakaryocytes, RAB31 reconstitution","pmids":["35839075"],"confidence":"Medium","gaps":["Direct RAB31–M6PR interaction not shown","Partial rescue leaves residual mechanism unexplained"]},{"year":2023,"claim":"Defining CLN3 as an M6PR interactor answered how receptor trafficking integrates with lysosomal reformation, showing CLN3 is required for correct CI-M6PR routing and proto-lysosome formation.","evidence":"Co-IP/proteomics, CLN3 loss- and gain-of-function, enzyme sorting assays and live imaging of lysosomal tubules","pmids":["37400440"],"confidence":"High","gaps":["Whether CLN3 acts on CD-M6PR not addressed","Structural basis of the CLN3–M6PR interaction unknown"]},{"year":2023,"claim":"Mapping the M6PR–HA2 interaction answered how the receptor's luminal domain serves viral entry, showing it directly promotes influenza envelope fusion with late-endosomal membranes.","evidence":"siRNA knockdown, Co-IP with HA, domain mapping, step-specific viral entry and NP nuclear accumulation assays","pmids":["38038885"],"confidence":"Medium","gaps":["Structural detail of the HA2–luminal-domain contact unresolved","Generality across virus strains not tested"]},{"year":2025,"claim":"Linking M6PR to STING degradation answered how the receptor can act on innate immune signaling, showing it binds STING and sorts it into endosomes to suppress senescence-associated signaling.","evidence":"Co-IP, endosomal co-localization, cellular thermal shift, M6PR siRNA knockdown rescue in a berberine context","pmids":["40714423"],"confidence":"Medium","gaps":["Whether STING is an M6P-tagged cargo or bound via another mode unknown","Single study; physiological relevance outside drug treatment unclear"]},{"year":2026,"claim":"Identifying ZNRF2-mediated degradation answered how receptor abundance is regulated, defining an mTORC1–ZNRF2–CD-M6PR axis that depletes the receptor and impairs lysosomal function in senescence.","evidence":"Structural prediction with validation, Co-IP, proteasome inhibitor, ZNRF2 knockdown/overexpression and mTORC1 inhibition","pmids":["42065825"],"confidence":"Medium","gaps":["Ubiquitination site on CD-M6PR not mapped","Single study"]},{"year":null,"claim":"How the diverse non-canonical roles (ASO escape, viral fusion, STING sorting) mechanistically relate to the receptor's core lysosomal-enzyme delivery function remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model for luminal-domain ligand promiscuity","Whether non-canonical cargoes use the M6P-binding site is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1,4,9]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1,2,6]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,2,4,9]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,4]}],"complexes":[],"partners":["GGA1","AP-1","RUFY1","SNX5","CLN3","GCC88","GCC2","ZNRF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P20645","full_name":"Cation-dependent mannose-6-phosphate receptor","aliases":["46 kDa mannose 6-phosphate receptor","MPR 46"],"length_aa":277,"mass_kda":31.0,"function":"Transport of phosphorylated lysosomal enzymes from the Golgi complex and the cell surface to lysosomes. Lysosomal enzymes bearing phosphomannosyl residues bind specifically to mannose-6-phosphate receptors in the Golgi apparatus and the resulting receptor-ligand complex is transported to an acidic prelyosomal compartment where the low pH mediates the dissociation of the complex","subcellular_location":"Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/P20645/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/M6PR","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ARL3","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"STX7","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/M6PR","total_profiled":1310},"omim":[{"mim_id":"616945","title":"CLAVESIN 2; CLVS2","url":"https://www.omim.org/entry/616945"},{"mim_id":"613401","title":"VPS33B-INTERACTING PROTEIN, APICAL-BASOLATERAL POLARITY REGULATOR, SPE39 HOMOLOG; VIPAS39","url":"https://www.omim.org/entry/613401"},{"mim_id":"611292","title":"CLAVESIN 1; CLVS1","url":"https://www.omim.org/entry/611292"},{"mim_id":"610893","title":"CHARGED MULTIVESICULAR BODY PROTEIN 2A; CHMP2A","url":"https://www.omim.org/entry/610893"},{"mim_id":"610223","title":"RAS AND RAB INTERACTOR 3; RIN3","url":"https://www.omim.org/entry/610223"}],"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/M6PR"},"hgnc":{"alias_symbol":["CD-MPR","CD-M6PR"],"prev_symbol":[]},"alphafold":{"accession":"P20645","domains":[{"cath_id":"2.70.130.10","chopping":"42-177","consensus_level":"high","plddt":93.8458,"start":42,"end":177},{"cath_id":"1.10.287","chopping":"187-242","consensus_level":"high","plddt":92.0177,"start":187,"end":242}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P20645","model_url":"https://alphafold.ebi.ac.uk/files/AF-P20645-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P20645-F1-predicted_aligned_error_v6.png","plddt_mean":84.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=M6PR","jax_strain_url":"https://www.jax.org/strain/search?query=M6PR"},"sequence":{"accession":"P20645","fasta_url":"https://rest.uniprot.org/uniprotkb/P20645.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P20645/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P20645"}},"corpus_meta":[{"pmid":"22540229","id":"PMC_22540229","title":"Retromer guides STxB and CD8-M6PR from early to recycling endosomes, EHD1 guides STxB from recycling endosome to Golgi.","date":"2012","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/22540229","citation_count":53,"is_preprint":false},{"pmid":"31840180","id":"PMC_31840180","title":"Golgi-endosome transport mediated by M6PR facilitates release of antisense oligonucleotides from endosomes.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31840180","citation_count":44,"is_preprint":false},{"pmid":"37400440","id":"PMC_37400440","title":"Loss of the batten disease protein CLN3 leads to mis-trafficking of M6PR and defective autophagic-lysosomal reformation.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37400440","citation_count":41,"is_preprint":false},{"pmid":"1964415","id":"PMC_1964415","title":"The recycling itinerary of the 46 kDa mannose 6-phosphate receptor--Golgi to late endosomes--coincides with that of the 215 kDa M6PR.","date":"1990","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1964415","citation_count":20,"is_preprint":false},{"pmid":"36632458","id":"PMC_36632458","title":"M6PR- and EphB4-Rich Exosomes Secreted by Serglycin-Overexpressing Esophageal Cancer Cells Promote Cancer Progression.","date":"2023","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36632458","citation_count":19,"is_preprint":false},{"pmid":"36282215","id":"PMC_36282215","title":"RUFY1 binds Arl8b and mediates endosome-to-TGN CI-M6PR retrieval for cargo sorting to lysosomes.","date":"2022","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/36282215","citation_count":16,"is_preprint":false},{"pmid":"15044437","id":"PMC_15044437","title":"The acidic cluster of the CK2 site of the cation-dependent mannose 6-phosphate receptor (CD-MPR) but not its phosphorylation is required for GGA1 and AP-1 binding.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15044437","citation_count":16,"is_preprint":false},{"pmid":"35929543","id":"PMC_35929543","title":"The uncoating of EV71 in mature late endosomes requires CD-M6PR.","date":"2022","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/35929543","citation_count":10,"is_preprint":false},{"pmid":"34604035","id":"PMC_34604035","title":"Gimap5 Inhibits Lung Cancer Growth by Interacting With M6PR.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34604035","citation_count":10,"is_preprint":false},{"pmid":"38038885","id":"PMC_38038885","title":"M6PR interacts with the HA2 subunit of influenza A virus to facilitate the fusion of viral and endosomal membranes.","date":"2023","source":"Science China. 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sensitizing tumor immunotherapy.","date":"2025","source":"Journal of colloid and interface science","url":"https://pubmed.ncbi.nlm.nih.gov/40929815","citation_count":1,"is_preprint":false},{"pmid":"29988026","id":"PMC_29988026","title":"Luminal/extracellular domains of chimeric CI-M6PR-C proteins interfere with their retrograde endosome-to-TGN trafficking in the transient expression system.","date":"2018","source":"Journal of biomedical research","url":"https://pubmed.ncbi.nlm.nih.gov/29988026","citation_count":1,"is_preprint":false},{"pmid":"28955638","id":"PMC_28955638","title":"Cloning of a functional mannose-6-phosphate reductase (M6PR) gene homolog from Egyptian celery plants (Apium graveolens): overexpression in non-mannitol producing plants resulted in mannitol accumulation in transgenic individuals.","date":"2017","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/28955638","citation_count":1,"is_preprint":false},{"pmid":"42065825","id":"PMC_42065825","title":"ZNRF2-mediated CD-M6PR degradation and lysosomal dysfunction aggravate cellular senescence and aging.","date":"2026","source":"GeroScience","url":"https://pubmed.ncbi.nlm.nih.gov/42065825","citation_count":0,"is_preprint":false},{"pmid":"41487160","id":"PMC_41487160","title":"Ligand Valency and Linker Design Dictate the Efficacy of CI-M6PR-Mediated Targeted Delivery of M6P-siRNA Conjugates.","date":"2025","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/41487160","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14152,"output_tokens":3560,"usd":0.047928,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11106,"output_tokens":3605,"usd":0.072828,"stage2_stop_reason":"end_turn"},"total_usd":0.120756,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"GGA1 binds to the CD-MPR cytoplasmic tail via the DXXLL motif (residues 61-65), with acidic residues Glu58 and Glu59 required for high-affinity binding in vitro; phosphorylation of Ser57 by CK2 has no influence on GGA1 or AP-1 binding. AP-1 binding requires Glu55, Glu56, Glu58, and Glu59 but is also independent of Ser57 phosphorylation. GGA1 binds with ~2.4-fold higher affinity than AP-1 to overlapping sorting signals on CD-MPR.\",\n      \"method\": \"In vitro binding assays with site-directed mutagenesis of CD-MPR cytoplasmic tail residues; in vivo co-immunoprecipitation of GGA1/AP-1 with CD-MPR mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding reconstitution with systematic mutagenesis plus in vivo co-IP validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15044437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The 46 kDa M6PR (CD-MPR) cycles between the Golgi complex (concentrated in middle/trans cisternae at steady state) and late endosomes (multivesicular endosomes), following the same intracellular itinerary as the 215 kDa CI-M6PR; both receptors co-localize in the same population of late endosomes after weak base treatment.\",\n      \"method\": \"Immunofluorescence and immunoperoxidase labeling with antipeptide antibodies to the C-terminal cytoplasmic domain; chloroquine/NH4Cl treatments; double-labeling for both M6PRs\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct subcellular fractionation/localization with multiple cell types and pharmacological perturbation, replicated across cell lines\",\n      \"pmids\": [\"1964415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD-M6PR (chimeric CD8-M6PR) retrograde trafficking from early endosomes to the Golgi requires transit through the recycling endosome; retromer is required for exit from early endosomes (ablation leaves cargo in EE), whereas EHD1 is not significantly required for CD8-M6PR trafficking from recycling endosome to TGN.\",\n      \"method\": \"Knockdown of retromer components and ablation of recycling endosomes; confocal immunofluorescence tracking of chimeric CD8-CI-M6PR cargo in HeLa cells\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined compartmental phenotype readout, single lab, two orthogonal perturbations\",\n      \"pmids\": [\"22540229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"M6PR shuttling mediated by GCC2 facilitates release of phosphorothioate antisense oligonucleotides (PS-ASOs) from late endosomes; M6PR co-localizes with PS-ASOs in late endosomes and binds PS-ASOs, and reduction of M6PR impairs PS-ASO endosomal escape and activity in human and mouse cells in vivo.\",\n      \"method\": \"siRNA knockdown of M6PR and GCC2; co-localization immunofluorescence; in vivo mouse subcutaneous PS-ASO treatment; functional ASO activity assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with functional readout, co-localization, and in vivo confirmation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31840180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RUFY1, recruited to endosomes via Arl8b-regulated interaction with Rab14, mediates CI-M6PR retrieval from endosomes to the TGN via dynein-dynactin; RUFY1 depletion delays CI-M6PR endosome-to-TGN retrieval and impairs delivery of newly synthesized hydrolases to lysosomes.\",\n      \"method\": \"Co-IP, siRNA depletion, dominant-negative and reconstitution experiments; co-localization with endosomal markers; dynein-dynactin interaction mapping\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, siRNA KD, reconstitution of RUFY1, multiple markers; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36282215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CLN3 interacts with CI-M6PR (cation-independent M6PR) and is required for its correct trafficking; CLN3 depletion causes mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation, while CLN3 overexpression promotes CI-M6PR-dependent lysosomal tubulation and proto-lysosome formation.\",\n      \"method\": \"Proteomic/co-IP interaction analysis; siRNA knockdown and overexpression of CLN3; lysosomal enzyme sorting assays; live imaging of lysosomal tubules\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/proteomics, loss- and gain-of-function with multiple phenotypic readouts, single lab but orthogonal methods\",\n      \"pmids\": [\"37400440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD-M6PR is present in mature late endosomes containing hSCARB2, RAB9, BMP, and LAMP2; siRNA knockdown of CD-M6PR impairs EV71 productive uncoating, placing CD-M6PR as a required host factor for EV71 uncoating in late endosomes.\",\n      \"method\": \"siRNA knockdown of CD-M6PR; immunofluorescence co-localization of M6PR with endosomal markers; viral growth/entry assays in hSCARB2-overexpressing cells\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA KD with viral functional readout and localization data, single lab, single study\",\n      \"pmids\": [\"35929543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"M6PR interacts with the ectodomain of the influenza A virus HA2 subunit via its lumenal domain; this interaction directly promotes fusion of the viral envelope with late endosomal membranes. siRNA knockdown of M6PR inhibited IAV replication by blocking membrane fusion without affecting viral attachment, internalization, early endosome trafficking, or late endosome acidification.\",\n      \"method\": \"siRNA knockdown; co-immunoprecipitation of M6PR with HA; domain-mapping experiments; viral entry step-specific assays; NP nuclear accumulation assays\",\n      \"journal\": \"Science China. Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP domain mapping, siRNA KD, stepwise entry dissection; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38038885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RAB31 downregulation (downstream of RUNX1 haplodeficiency) impairs trafficking of M6PR at the level of early endosomes in megakaryocytes, resulting in enlarged early endosomes; reconstitution of RAB31 partially reverses this endosomal defect.\",\n      \"method\": \"siRNA and CRISPR/Cas9 knockdown of RUNX1 and RAB31; immunofluorescence for EEA1/CD63; patient-derived iPSC-megakaryocytes; RAB31 reconstitution\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD, patient-derived model, reconstitution rescue, multiple markers; single lab\",\n      \"pmids\": [\"35839075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GCC88 (trans-Golgi golgin tethering factor) is required for endosome-to-TGN retrograde transport of CI-M6PR; GCC88 knockout reduces cellular CI-M6PR levels, impairs cathepsin-D processing (a CI-M6PR-dependent lysosomal hydrolase), and reduces lysosomal proteolytic capacity.\",\n      \"method\": \"GCC88 knockout cells; immunofluorescence and western blot of CI-M6PR; cathepsin-D maturation assay; lysosomal protease activity assay\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KO with defined functional readout, single lab, single study\",\n      \"pmids\": [\"30791178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In senescent cells, CD-M6PR undergoes accelerated proteasome-mediated degradation driven by the E3 ubiquitin ligase ZNRF2 (whose expression is elevated via mTORC1 activation under stress); this ZNRF2-mediated CD-M6PR reduction impairs lysosomal enzyme trafficking and autolysosomal function, exacerbating senescence via a mTORC1-ZNRF2-CD-M6PR axis.\",\n      \"method\": \"Structural prediction and experimental validation; immunoprecipitation; Western blot; proteasome inhibitor experiments; ZNRF2 knockdown/overexpression; mTORC1 inhibition\",\n      \"journal\": \"GeroScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, pharmacological and genetic perturbation, structural prediction with experimental validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42065825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Berberine upregulates M6PR specifically in senescent cells; upregulated M6PR binds STING and sorts it into endosomes for degradation, suppressing STING signaling and senescence-associated secretory phenotypes. M6PR knockdown abrogates berberine's anti-senescence effects even when STING expression is reversed.\",\n      \"method\": \"Immunoprecipitation of M6PR-STING; immunofluorescence for endosomal co-localization; cell thermal shift assay; M6PR siRNA knockdown rescue experiments; Western blot for STING/IFN-β\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, cellular thermal shift, KD rescue; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40714423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The luminal/extracellular domain of CI-M6PR influences its TGN targeting: partial deletion or replacement of the luminal domain misdirects the receptor to non-TGN compartments, while a short HA-tagged C-terminal tail construct (HA-hCI-M6PR-tail) traffics preferentially to TGN. The retromer complex regulates trafficking of the luminal-truncated form through interaction with SNX5.\",\n      \"method\": \"Deletion and chimeric domain-swap mutants of CI-M6PR; immunofluorescence localization in transfected cells; co-immunoprecipitation with retromer/SNX5\",\n      \"journal\": \"Journal of biomedical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — domain-swap mutagenesis with localization readout and Co-IP; single lab, single study\",\n      \"pmids\": [\"29988026\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD-MPR (M6PR) cycles between the trans-Golgi network and late endosomes to deliver mannose-6-phosphate-tagged lysosomal enzymes; its cytoplasmic tail contains overlapping sorting signals (DXXLL motif, acidic cluster) that recruit GGA1 (higher affinity) and AP-1 for TGN-to-endosome transport, while retromer (via SNX5/RUFY1-dynein) and golgins (GCC88, GCC2) mediate retrograde endosome-to-TGN retrieval through the recycling endosome; its stability is controlled by the E3 ligase ZNRF2 (elevated by mTORC1 in senescence) that targets it for proteasomal degradation; beyond lysosomal biogenesis, M6PR also facilitates endosomal escape of antisense oligonucleotides, promotes viral membrane fusion (IAV HA2 interaction), and mediates STING endosomal sorting for degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"M6PR (CD-MPR) is a cargo receptor that cycles between the trans-Golgi network and late endosomes to deliver mannose-6-phosphate-tagged lysosomal enzymes, following an itinerary shared with the larger cation-independent receptor [#1]. Anterograde TGN-to-endosome sorting is directed by overlapping signals in its cytoplasmic tail: a DXXLL motif (residues 61-65) flanked by acidic residues recruits GGA1 with higher affinity than AP-1, with both interactions independent of CK2-mediated Ser57 phosphorylation [#0]. Retrograde retrieval from endosomes to the TGN proceeds through the recycling endosome and depends on retromer for early-endosome exit [#2], with RUFY1 (recruited via Arl8b/Rab14) coupling cargo to dynein-dynactin [#4] and golgin tethers GCC88 and GCC2 completing TGN delivery [#9, #3]; loss of these factors reduces receptor levels, impairs cathepsin-D processing, and lowers lysosomal proteolytic capacity [#9]. Receptor abundance is further controlled by accelerated proteasomal degradation via the E3 ligase ZNRF2 in senescent cells, impairing lysosomal enzyme trafficking and autolysosomal function [#10]. Beyond lysosomal biogenesis, M6PR's luminal domain promotes influenza A virus envelope fusion with late-endosomal membranes through interaction with the HA2 ectodomain [#7], facilitates endosomal escape of phosphorothioate antisense oligonucleotides [#3], and binds STING to sort it into endosomes for degradation, suppressing STING signaling [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Establishing where the 46 kDa receptor resides answered whether it shares a trafficking route with the larger M6PR, defining its itinerary between Golgi and late endosomes.\",\n      \"evidence\": \"Immunofluorescence/immunoperoxidase with anti-cytoplasmic-tail antibodies and base treatment across cell types\",\n      \"pmids\": [\"1964415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular machinery directing each transport step\", \"Steady-state localization does not establish kinetics of cycling\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapping the cytoplasmic-tail sorting signals answered how adaptors are recruited for anterograde transport, showing GGA1 and AP-1 bind overlapping acidic/DXXLL signals with distinct affinities and independent of Ser57 phosphorylation.\",\n      \"evidence\": \"In vitro binding with site-directed mutagenesis plus in vivo co-IP of GGA1/AP-1 with CD-MPR mutants\",\n      \"pmids\": [\"15044437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of differential GGA1 vs AP-1 affinity for cargo flux not quantified\", \"Role of Ser57 phosphorylation, if any, left unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Dissecting retrograde transport answered which compartments and factors are required, placing retromer at early-endosome exit and the recycling endosome as an obligatory waystation.\",\n      \"evidence\": \"siRNA knockdown of retromer and recycling-endosome ablation with confocal tracking of chimeric CD8-M6PR in HeLa\",\n      \"pmids\": [\"22540229\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Used a chimeric reporter rather than endogenous receptor\", \"Single cell line; EHD1-independence not mechanistically explained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Testing the luminal domain answered whether TGN targeting information lies outside the cytoplasmic tail, showing the luminal domain influences correct targeting and links retromer regulation to SNX5.\",\n      \"evidence\": \"Domain-deletion/chimera mutants with localization imaging and co-IP with retromer/SNX5\",\n      \"pmids\": [\"29988026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the luminal domain dictates sorting unknown\", \"Single study, overexpressed constructs\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Knocking out the golgin GCC88 answered whether trans-Golgi tethering is required for retrieval, linking receptor recycling to lysosomal hydrolase maturation and proteolytic capacity.\",\n      \"evidence\": \"GCC88 knockout cells with CI-M6PR western/IF, cathepsin-D maturation and lysosomal protease assays\",\n      \"pmids\": [\"30791178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GCC88–M6PR contact not demonstrated\", \"Single study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identifying RUFY1 answered how endosome-to-TGN cargo is coupled to a motor, showing Arl8b/Rab14-recruited RUFY1 links the receptor to dynein-dynactin for retrieval and hydrolase delivery.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA depletion, dominant-negative and reconstitution with endosomal markers\",\n      \"pmids\": [\"36282215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect RUFY1–M6PR association not fully resolved\", \"Studied for CI-M6PR; applicability to CD-M6PR not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linking RAB31 to receptor trafficking answered a disease-relevant question, showing RAB31 loss downstream of RUNX1 haplodeficiency disrupts M6PR transit at early endosomes in megakaryocytes.\",\n      \"evidence\": \"siRNA/CRISPR knockdown of RUNX1 and RAB31, patient iPSC-megakaryocytes, RAB31 reconstitution\",\n      \"pmids\": [\"35839075\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RAB31–M6PR interaction not shown\", \"Partial rescue leaves residual mechanism unexplained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining CLN3 as an M6PR interactor answered how receptor trafficking integrates with lysosomal reformation, showing CLN3 is required for correct CI-M6PR routing and proto-lysosome formation.\",\n      \"evidence\": \"Co-IP/proteomics, CLN3 loss- and gain-of-function, enzyme sorting assays and live imaging of lysosomal tubules\",\n      \"pmids\": [\"37400440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CLN3 acts on CD-M6PR not addressed\", \"Structural basis of the CLN3–M6PR interaction unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapping the M6PR–HA2 interaction answered how the receptor's luminal domain serves viral entry, showing it directly promotes influenza envelope fusion with late-endosomal membranes.\",\n      \"evidence\": \"siRNA knockdown, Co-IP with HA, domain mapping, step-specific viral entry and NP nuclear accumulation assays\",\n      \"pmids\": [\"38038885\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural detail of the HA2–luminal-domain contact unresolved\", \"Generality across virus strains not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linking M6PR to STING degradation answered how the receptor can act on innate immune signaling, showing it binds STING and sorts it into endosomes to suppress senescence-associated signaling.\",\n      \"evidence\": \"Co-IP, endosomal co-localization, cellular thermal shift, M6PR siRNA knockdown rescue in a berberine context\",\n      \"pmids\": [\"40714423\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STING is an M6P-tagged cargo or bound via another mode unknown\", \"Single study; physiological relevance outside drug treatment unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identifying ZNRF2-mediated degradation answered how receptor abundance is regulated, defining an mTORC1–ZNRF2–CD-M6PR axis that depletes the receptor and impairs lysosomal function in senescence.\",\n      \"evidence\": \"Structural prediction with validation, Co-IP, proteasome inhibitor, ZNRF2 knockdown/overexpression and mTORC1 inhibition\",\n      \"pmids\": [\"42065825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination site on CD-M6PR not mapped\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse non-canonical roles (ASO escape, viral fusion, STING sorting) mechanistically relate to the receptor's core lysosomal-enzyme delivery function remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model for luminal-domain ligand promiscuity\", \"Whether non-canonical cargoes use the M6P-binding site is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1, 4, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1, 2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 2, 4, 9]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GGA1\", \"AP-1\", \"RUFY1\", \"SNX5\", \"CLN3\", \"GCC88\", \"GCC2\", \"ZNRF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}