{"gene":"FBXO27","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2017,"finding":"FBXO27 is a glycoprotein-specific F-box protein that forms an SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex (SCF^FBXO27) and ubiquitinates glycoproteins exposed on damaged lysosomal membranes to direct damaged lysosomes for autophagy (lysophagy). Substrates identified include SNARE proteins VAMP3 and VAMP7, and lysosomal proteins LAMP1, LAMP2, GNS, PSAP, and TMEM192. LAMP2 ubiquitination was shown to enhance autophagic machinery recruitment to damaged lysosomes.","method":"Co-immunoprecipitation, ubiquitination screen upon lysosomal damage, FBXO27 overexpression functional assay, substrate identification by MS","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, substrate screen with multiple orthogonal methods, functional validation of downstream effect; replicated by other labs citing this work","pmids":["28743755"],"is_preprint":false},{"year":2017,"finding":"FBXO27 is subject to N-myristoylation, which localizes it to membranes and allows it to rapidly accumulate around damaged lysosomes upon lysosomal damage, distinguishing it from F-box proteins in other SCF complexes.","method":"N-myristoylation characterization, membrane localization assay, live-cell imaging of FBXO27 recruitment to damaged lysosomes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence, within the same rigorous study","pmids":["28743755"],"is_preprint":false},{"year":2008,"finding":"FBXO27 (as part of the FBA family) binds high mannose glycoproteins through a conserved G domain; site-directed mutagenesis of two aromatic amino acids in the G domain demonstrated that the hydrophobic pocket formed by these residues is necessary for high-affinity glycan binding. FBXO27 co-precipitates components of the canonical SCF complex (Skp1, Cullin1, and Rbx1).","method":"Glycan arrays, site-directed mutagenesis of G domain aromatic residues, co-immunoprecipitation of SCF components","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding assay with mutagenesis and glycan arrays; multiple orthogonal approaches in a single study","pmids":["18203720"],"is_preprint":false},{"year":2011,"finding":"FBXO27 (Fbg5/Fbs3) forms SCF complexes but requires co-expression with Skp1 to properly fold and bind N-glycoproteins; Skp1 stabilizes the conformation of FBXO27, prevents aggregate formation, and increases its cellular concentration, enabling substrate binding.","method":"Co-expression and co-immunoprecipitation, ConA lectin binding assay, aggregate formation analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — functional binding assay with mechanistic follow-up; single lab, moderate evidence","pmids":["21640084"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of the Skp1-FBG3 (FBXO44) complex revealed that FBXO27 (Fbs3/FBG5) recognizes N-glycans via a substrate-binding domain composed of a 10-stranded antiparallel β-sandwich, and structure-based mutational analysis showed that distinct loop conformations in FBXO44 prevent formation of the carbohydrate-binding pocket present in FBXO27/Fbs1.","method":"X-ray crystallography (2.6 Å), structure-based mutational analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 — crystal structure with mutagenesis, but directly resolves homolog FBG3/FBXO44, providing structural context for FBXO27 glycan-binding mechanism by comparison","pmids":["26460611"],"is_preprint":false},{"year":2023,"finding":"CREG1 inhibits FBXO27 protein expression, thereby preventing FBXO27-mediated ubiquitination and degradation of LAMP2, which promotes autophagy in cardiomyocytes. This CREG1-FBXO27-LAMP2 axis is relevant in diabetic cardiomyopathy.","method":"Genetic overexpression and knockdown in cardiomyocytes, western blotting, LAMP2 overexpression rescue experiment","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional epistasis in cell model with rescue experiment; single lab, moderate evidence","pmids":["37658156"],"is_preprint":false}],"current_model":"FBXO27 is an N-myristoylated, glycoprotein-specific F-box protein that assembles into an SCF^FBXO27 ubiquitin ligase complex; upon lysosomal membrane damage, its membrane localization (via N-myristoylation) allows rapid recruitment to ruptured lysosomes where it ubiquitinates exposed glycoproteins (including LAMP1, LAMP2, VAMP3, VAMP7) to recruit autophagic machinery and drive lysophagy, with substrate binding mediated by a conserved hydrophobic G-domain pocket that recognizes high-mannose N-glycans."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing that FBXO27 is a glycan-binding F-box protein answered how it selects substrates: a conserved G-domain hydrophobic pocket formed by two aromatic residues binds high-mannose N-glycans, and the protein assembles with canonical SCF components (SKP1, CUL1, RBX1).","evidence":"Glycan arrays, site-directed mutagenesis of G-domain aromatic residues, co-immunoprecipitation of SCF components in vitro","pmids":["18203720"],"confidence":"High","gaps":["No physiological substrates identified at this stage","Cellular context for glycoprotein ubiquitination unknown","No structural model of FBXO27 itself"]},{"year":2011,"claim":"Demonstrating that SKP1 co-expression is required for FBXO27 folding, stability, and glycoprotein-binding competence resolved why isolated FBXO27 aggregates and fails to bind substrates.","evidence":"Co-expression/co-immunoprecipitation, ConA lectin binding assay, aggregate formation analysis","pmids":["21640084"],"confidence":"Medium","gaps":["Single-lab finding without independent replication","Structural basis for SKP1-dependent conformational stabilization not resolved","In vivo relevance of this dependency not tested"]},{"year":2015,"claim":"Crystallography of the homologous SKP1–FBG3 complex provided structural context for how the 10-stranded β-sandwich substrate-binding domain accommodates glycans in FBXO27, and mutagenesis explained why the related FBXO44 lacks glycan-binding activity.","evidence":"X-ray crystallography (2.6 Å) of SKP1–FBXO44, structure-based mutational analysis comparing FBXO27 and FBXO44","pmids":["26460611"],"confidence":"Medium","gaps":["Structure is of the FBXO44 homolog, not FBXO27 directly","No co-crystal with glycan substrate","Loop conformations in FBXO27 inferred by comparison rather than determined"]},{"year":2017,"claim":"Identifying FBXO27 as a lysophagy effector resolved its physiological function: N-myristoylation targets it to membranes, enabling rapid accumulation at damaged lysosomes where SCF^FBXO27 ubiquitinates exposed glycoproteins (LAMP1, LAMP2, VAMP3, VAMP7) to recruit autophagic machinery.","evidence":"N-myristoylation characterization, live-cell imaging of lysosome recruitment, Co-IP, ubiquitination screen upon LLOMe-induced damage, substrate identification by mass spectrometry","pmids":["28743755"],"confidence":"High","gaps":["Relative contribution of individual substrates to lysophagy efficiency not dissected","Functional redundancy with other glycoprotein-targeting E3 ligases (e.g., FBXO2) during lysophagy unclear","In vivo lysophagy phenotype of FBXO27 knockout not reported"]},{"year":2023,"claim":"Placing FBXO27 downstream of CREG1 in cardiomyocytes revealed an upstream regulatory axis: CREG1 represses FBXO27 protein levels, preventing LAMP2 ubiquitination and thereby sustaining autophagy, with relevance to diabetic cardiomyopathy.","evidence":"Genetic overexpression/knockdown in cardiomyocytes, western blotting, LAMP2 rescue experiments","pmids":["37658156"],"confidence":"Medium","gaps":["Mechanism by which CREG1 inhibits FBXO27 expression (transcriptional vs. post-translational) not defined","Single-lab study without independent replication","In vivo cardiac phenotype of FBXO27 manipulation not demonstrated"]},{"year":null,"claim":"Key unresolved questions include the direct crystal structure of FBXO27 bound to glycan substrates, in vivo phenotypic consequences of FBXO27 loss in lysophagy and disease models, and the full repertoire of regulatory inputs controlling FBXO27 expression and activity.","evidence":"","pmids":[],"confidence":"Low","gaps":["No FBXO27 crystal structure or cryo-EM model available","No in vivo knockout phenotype reported","Regulation of FBXO27 beyond CREG1 is uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2]}],"complexes":["SCF^FBXO27 (SKP1–CUL1–RBX1–FBXO27)"],"partners":["SKP1","CUL1","RBX1","LAMP1","LAMP2","VAMP3","VAMP7","CREG1"],"other_free_text":[]},"mechanistic_narrative":"FBXO27 is an N-myristoylated F-box protein that assembles into an SCF^FBXO27 (SKP1–CUL1–RBX1–FBXO27) ubiquitin ligase complex and selectively ubiquitinates glycoproteins exposed on damaged lysosomal membranes to promote lysophagy. Its substrate-binding G domain contains a conserved hydrophobic pocket formed by aromatic residues that recognizes high-mannose N-glycans, and proper folding of this domain requires co-expression with SKP1 [PMID:18203720, PMID:21640084]. N-myristoylation targets FBXO27 to membranes, enabling rapid recruitment to ruptured lysosomes where it ubiquitinates LAMP1, LAMP2, VAMP3, VAMP7, and other glycoproteins, with LAMP2 ubiquitination enhancing autophagic machinery recruitment [PMID:28743755]. A CREG1–FBXO27–LAMP2 regulatory axis controls autophagy in cardiomyocytes and is implicated in diabetic cardiomyopathy [PMID:37658156]."},"prefetch_data":{"uniprot":{"accession":"Q8NI29","full_name":"F-box only protein 27","aliases":["F-box/G-domain protein 5"],"length_aa":283,"mass_kda":31.6,"function":"Substrate-recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex. Able to recognize and bind denatured glycoproteins, which are modified with complex-type oligosaccharides","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8NI29/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FBXO27","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FBXO27","total_profiled":1310},"omim":[{"mim_id":"609099","title":"F-BOX ONLY PROTEIN 27; FBXO27","url":"https://www.omim.org/entry/609099"},{"mim_id":"609094","title":"F-BOX ONLY PROTEIN 17; FBXO17","url":"https://www.omim.org/entry/609094"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skin 1","ntpm":35.4}],"url":"https://www.proteinatlas.org/search/FBXO27"},"hgnc":{"alias_symbol":["Fbg5","Fbx27"],"prev_symbol":[]},"alphafold":{"accession":"Q8NI29","domains":[{"cath_id":"1.20.1280.50","chopping":"28-106","consensus_level":"high","plddt":90.0234,"start":28,"end":106},{"cath_id":"2.60.120.260","chopping":"113-279","consensus_level":"high","plddt":96.6011,"start":113,"end":279}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NI29","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NI29-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NI29-F1-predicted_aligned_error_v6.png","plddt_mean":91.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FBXO27","jax_strain_url":"https://www.jax.org/strain/search?query=FBXO27"},"sequence":{"accession":"Q8NI29","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NI29.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NI29/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NI29"}},"corpus_meta":[{"pmid":"32048886","id":"PMC_32048886","title":"Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles.","date":"2020","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/32048886","citation_count":339,"is_preprint":false},{"pmid":"28743755","id":"PMC_28743755","title":"Ubiquitination of exposed glycoproteins by SCFFBXO27 directs damaged lysosomes for autophagy.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/28743755","citation_count":113,"is_preprint":false},{"pmid":"18203720","id":"PMC_18203720","title":"Diversity in tissue expression, substrate binding, and SCF complex formation for a lectin family of ubiquitin ligases.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18203720","citation_count":65,"is_preprint":false},{"pmid":"37658156","id":"PMC_37658156","title":"The CREG1-FBXO27-LAMP2 axis alleviates diabetic cardiomyopathy by promoting autophagy in cardiomyocytes.","date":"2023","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37658156","citation_count":31,"is_preprint":false},{"pmid":"12383498","id":"PMC_12383498","title":"A new subfamily of structurally related human F-box proteins.","date":"2002","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/12383498","citation_count":31,"is_preprint":false},{"pmid":"37357416","id":"PMC_37357416","title":"TRIM16-mediated lysophagy suppresses high-glucose-accumulated neuronal Aβ.","date":"2023","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/37357416","citation_count":29,"is_preprint":false},{"pmid":"21640084","id":"PMC_21640084","title":"Skp1 stabilizes the conformation of F-box proteins.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21640084","citation_count":26,"is_preprint":false},{"pmid":"34841657","id":"PMC_34841657","title":"Non-coding RNAs and related molecules associated with form-deprivation myopia in mice.","date":"2021","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34841657","citation_count":18,"is_preprint":false},{"pmid":"26460611","id":"PMC_26460611","title":"The Structural Differences between a Glycoprotein Specific F-Box Protein Fbs1 and Its Homologous Protein FBG3.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26460611","citation_count":15,"is_preprint":false},{"pmid":"39744815","id":"PMC_39744815","title":"Linear ubiquitination at damaged lysosomes induces local NFKB activation and controls cell survival.","date":"2025","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/39744815","citation_count":9,"is_preprint":false},{"pmid":"36338969","id":"PMC_36338969","title":"Caveolin-1 rs1997623 variant and adult metabolic syndrome-Assessing the association in three ethnic cohorts of Arabs, South Asians and South East Asians.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36338969","citation_count":5,"is_preprint":false},{"pmid":"39577754","id":"PMC_39577754","title":"Role for the F-box proteins in heart diseases.","date":"2024","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/39577754","citation_count":4,"is_preprint":false},{"pmid":"39923360","id":"PMC_39923360","title":"Endoplasmic reticulum stress and unfolded protein response play roles in recurrent pregnancy loss: A bioinformatics study.","date":"2025","source":"Journal of reproductive immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39923360","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10272,"output_tokens":1622,"usd":0.027573},"stage2":{"model":"claude-opus-4-6","input_tokens":4865,"output_tokens":1916,"usd":0.108338},"total_usd":0.135911,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"FBXO27 is a glycoprotein-specific F-box protein that forms an SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex (SCF^FBXO27) and ubiquitinates glycoproteins exposed on damaged lysosomal membranes to direct damaged lysosomes for autophagy (lysophagy). Substrates identified include SNARE proteins VAMP3 and VAMP7, and lysosomal proteins LAMP1, LAMP2, GNS, PSAP, and TMEM192. LAMP2 ubiquitination was shown to enhance autophagic machinery recruitment to damaged lysosomes.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination screen upon lysosomal damage, FBXO27 overexpression functional assay, substrate identification by MS\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, substrate screen with multiple orthogonal methods, functional validation of downstream effect; replicated by other labs citing this work\",\n      \"pmids\": [\"28743755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FBXO27 is subject to N-myristoylation, which localizes it to membranes and allows it to rapidly accumulate around damaged lysosomes upon lysosomal damage, distinguishing it from F-box proteins in other SCF complexes.\",\n      \"method\": \"N-myristoylation characterization, membrane localization assay, live-cell imaging of FBXO27 recruitment to damaged lysosomes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence, within the same rigorous study\",\n      \"pmids\": [\"28743755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FBXO27 (as part of the FBA family) binds high mannose glycoproteins through a conserved G domain; site-directed mutagenesis of two aromatic amino acids in the G domain demonstrated that the hydrophobic pocket formed by these residues is necessary for high-affinity glycan binding. FBXO27 co-precipitates components of the canonical SCF complex (Skp1, Cullin1, and Rbx1).\",\n      \"method\": \"Glycan arrays, site-directed mutagenesis of G domain aromatic residues, co-immunoprecipitation of SCF components\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding assay with mutagenesis and glycan arrays; multiple orthogonal approaches in a single study\",\n      \"pmids\": [\"18203720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FBXO27 (Fbg5/Fbs3) forms SCF complexes but requires co-expression with Skp1 to properly fold and bind N-glycoproteins; Skp1 stabilizes the conformation of FBXO27, prevents aggregate formation, and increases its cellular concentration, enabling substrate binding.\",\n      \"method\": \"Co-expression and co-immunoprecipitation, ConA lectin binding assay, aggregate formation analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional binding assay with mechanistic follow-up; single lab, moderate evidence\",\n      \"pmids\": [\"21640084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of the Skp1-FBG3 (FBXO44) complex revealed that FBXO27 (Fbs3/FBG5) recognizes N-glycans via a substrate-binding domain composed of a 10-stranded antiparallel β-sandwich, and structure-based mutational analysis showed that distinct loop conformations in FBXO44 prevent formation of the carbohydrate-binding pocket present in FBXO27/Fbs1.\",\n      \"method\": \"X-ray crystallography (2.6 Å), structure-based mutational analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis, but directly resolves homolog FBG3/FBXO44, providing structural context for FBXO27 glycan-binding mechanism by comparison\",\n      \"pmids\": [\"26460611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CREG1 inhibits FBXO27 protein expression, thereby preventing FBXO27-mediated ubiquitination and degradation of LAMP2, which promotes autophagy in cardiomyocytes. This CREG1-FBXO27-LAMP2 axis is relevant in diabetic cardiomyopathy.\",\n      \"method\": \"Genetic overexpression and knockdown in cardiomyocytes, western blotting, LAMP2 overexpression rescue experiment\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional epistasis in cell model with rescue experiment; single lab, moderate evidence\",\n      \"pmids\": [\"37658156\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FBXO27 is an N-myristoylated, glycoprotein-specific F-box protein that assembles into an SCF^FBXO27 ubiquitin ligase complex; upon lysosomal membrane damage, its membrane localization (via N-myristoylation) allows rapid recruitment to ruptured lysosomes where it ubiquitinates exposed glycoproteins (including LAMP1, LAMP2, VAMP3, VAMP7) to recruit autophagic machinery and drive lysophagy, with substrate binding mediated by a conserved hydrophobic G-domain pocket that recognizes high-mannose N-glycans.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FBXO27 is an N-myristoylated F-box protein that assembles into an SCF^FBXO27 (SKP1–CUL1–RBX1–FBXO27) ubiquitin ligase complex and selectively ubiquitinates glycoproteins exposed on damaged lysosomal membranes to promote lysophagy. Its substrate-binding G domain contains a conserved hydrophobic pocket formed by aromatic residues that recognizes high-mannose N-glycans, and proper folding of this domain requires co-expression with SKP1 [PMID:18203720, PMID:21640084]. N-myristoylation targets FBXO27 to membranes, enabling rapid recruitment to ruptured lysosomes where it ubiquitinates LAMP1, LAMP2, VAMP3, VAMP7, and other glycoproteins, with LAMP2 ubiquitination enhancing autophagic machinery recruitment [PMID:28743755]. A CREG1–FBXO27–LAMP2 regulatory axis controls autophagy in cardiomyocytes and is implicated in diabetic cardiomyopathy [PMID:37658156].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that FBXO27 is a glycan-binding F-box protein answered how it selects substrates: a conserved G-domain hydrophobic pocket formed by two aromatic residues binds high-mannose N-glycans, and the protein assembles with canonical SCF components (SKP1, CUL1, RBX1).\",\n      \"evidence\": \"Glycan arrays, site-directed mutagenesis of G-domain aromatic residues, co-immunoprecipitation of SCF components in vitro\",\n      \"pmids\": [\"18203720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No physiological substrates identified at this stage\",\n        \"Cellular context for glycoprotein ubiquitination unknown\",\n        \"No structural model of FBXO27 itself\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that SKP1 co-expression is required for FBXO27 folding, stability, and glycoprotein-binding competence resolved why isolated FBXO27 aggregates and fails to bind substrates.\",\n      \"evidence\": \"Co-expression/co-immunoprecipitation, ConA lectin binding assay, aggregate formation analysis\",\n      \"pmids\": [\"21640084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding without independent replication\",\n        \"Structural basis for SKP1-dependent conformational stabilization not resolved\",\n        \"In vivo relevance of this dependency not tested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Crystallography of the homologous SKP1–FBG3 complex provided structural context for how the 10-stranded β-sandwich substrate-binding domain accommodates glycans in FBXO27, and mutagenesis explained why the related FBXO44 lacks glycan-binding activity.\",\n      \"evidence\": \"X-ray crystallography (2.6 Å) of SKP1–FBXO44, structure-based mutational analysis comparing FBXO27 and FBXO44\",\n      \"pmids\": [\"26460611\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structure is of the FBXO44 homolog, not FBXO27 directly\",\n        \"No co-crystal with glycan substrate\",\n        \"Loop conformations in FBXO27 inferred by comparison rather than determined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying FBXO27 as a lysophagy effector resolved its physiological function: N-myristoylation targets it to membranes, enabling rapid accumulation at damaged lysosomes where SCF^FBXO27 ubiquitinates exposed glycoproteins (LAMP1, LAMP2, VAMP3, VAMP7) to recruit autophagic machinery.\",\n      \"evidence\": \"N-myristoylation characterization, live-cell imaging of lysosome recruitment, Co-IP, ubiquitination screen upon LLOMe-induced damage, substrate identification by mass spectrometry\",\n      \"pmids\": [\"28743755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contribution of individual substrates to lysophagy efficiency not dissected\",\n        \"Functional redundancy with other glycoprotein-targeting E3 ligases (e.g., FBXO2) during lysophagy unclear\",\n        \"In vivo lysophagy phenotype of FBXO27 knockout not reported\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placing FBXO27 downstream of CREG1 in cardiomyocytes revealed an upstream regulatory axis: CREG1 represses FBXO27 protein levels, preventing LAMP2 ubiquitination and thereby sustaining autophagy, with relevance to diabetic cardiomyopathy.\",\n      \"evidence\": \"Genetic overexpression/knockdown in cardiomyocytes, western blotting, LAMP2 rescue experiments\",\n      \"pmids\": [\"37658156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which CREG1 inhibits FBXO27 expression (transcriptional vs. post-translational) not defined\",\n        \"Single-lab study without independent replication\",\n        \"In vivo cardiac phenotype of FBXO27 manipulation not demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the direct crystal structure of FBXO27 bound to glycan substrates, in vivo phenotypic consequences of FBXO27 loss in lysophagy and disease models, and the full repertoire of regulatory inputs controlling FBXO27 expression and activity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No FBXO27 crystal structure or cryo-EM model available\",\n        \"No in vivo knockout phenotype reported\",\n        \"Regulation of FBXO27 beyond CREG1 is uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\n      \"SCF^FBXO27 (SKP1–CUL1–RBX1–FBXO27)\"\n    ],\n    \"partners\": [\n      \"SKP1\",\n      \"CUL1\",\n      \"RBX1\",\n      \"LAMP1\",\n      \"LAMP2\",\n      \"VAMP3\",\n      \"VAMP7\",\n      \"CREG1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}