{"gene":"SH3GLB2","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":2001,"finding":"SH3GLB2 was identified as a binding partner of SH3GLB1 in a yeast two-hybrid screen; the interaction requires a core coiled-coil-type region, while the SH3 domain is not involved in homo- or heterodimer formation. SH3GLB2 colocalizes with Bax in the cytoplasmic compartment and is excluded from the nucleus.","method":"Yeast two-hybrid screen, domain mapping, subcellular localization","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid with domain-mapping experiments and localization, single lab, two orthogonal methods","pmids":["11161816"],"is_preprint":false},{"year":2001,"finding":"SH3GLB1 and SH3GLB2 do not significantly influence the onset or time course of Bax-mediated apoptosis in HeLa or 293T cells (negative result).","method":"Overexpression in HeLa and 293T cells with apoptosis assay","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay in two cell lines, single lab, negative finding explicitly reported","pmids":["11161816"],"is_preprint":false},{"year":2017,"finding":"Endophilin B2 (SH3GLB2) positively regulates endosome maturation: its deficiency suppresses endosome acidification, EGFR degradation, autophagic flux, and influenza A viral RNA nuclear entry/replication, without affecting endocytic internalization or lysosomal function. The N-BAR domain is implicated in membrane curvature regulation of intracellular membrane dynamics.","method":"Genetic knockout (B2-deficient cells/mice), endosome acidification assay, EGFR degradation assay, autophagic flux assay, viral RNA nuclear entry assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional readouts in both in vitro and in vivo genetic knockout models, single lab but rigorous multi-method study","pmids":["28455444"],"is_preprint":false},{"year":2017,"finding":"SH3GLB2 (endophilin B2) is dispensable for mitochondrial apoptosis despite having intracellular localization and tissue distribution similar to endophilin B1 (negative result).","method":"Genetic knockout with apoptosis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with direct apoptosis readout, single lab, explicit negative result","pmids":["28455444"],"is_preprint":false},{"year":2017,"finding":"Loss of endophilin B2 (SH3GLB2) in mice enhances recovery from severe H1N1 influenza infection, associated with induction of surfactant protein genes, ABCA3, GM-CSF, podoplanin, caveolin, CEBPα/β/δ mRNAs, restoration of alveolar macrophages, and recruitment of CD4+ lymphocytes, indicating a role for SH3GLB2 in regulating lung homeostasis and alveolar immune cell recovery.","method":"B2-deficient mouse model, intranasal H1N1 infection, flow cytometry, gene expression analysis, respiratory mechanics assessment","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic knockout with multiple orthogonal readouts (survival, immune cell profiling, gene expression, mechanics), single lab","pmids":["28779131"],"is_preprint":false},{"year":2017,"finding":"SH3GLB2 protein aggregates in brain tissue of Alzheimer's disease triple-transgenic mice; Zfra peptide blocks this aggregation and restores memory, and Zfra was shown to bind cytosolic proteins to accelerate their degradation in a ubiquitin/proteasome-independent manner in vitro.","method":"In vivo 3xTg mouse model with peptide injection, in vitro aggregation assay, behavioral testing","journal":"Alzheimer's & dementia (New York, N. Y.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — SH3GLB2 aggregation observed but mechanism of SH3GLB2 itself not directly dissected; the described mechanism is for Zfra, single lab","pmids":["29067327"],"is_preprint":false},{"year":2022,"finding":"SH3GLB2 aggregation occurs downstream of TRAPPC6AΔ (TPC6AΔ) and TIAF1 in a protein cascade triggered by MPP+ (a Parkinson's disease neurotoxin) in neuroblastoma SK-N-SH cells, placing SH3GLB2 in a neurodegeneration-associated aggregation pathway.","method":"Cell treatment with MPP+, protein aggregation assay in SK-N-SH neuroblastoma cells","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (aggregation assay), pathway placement inferred from co-aggregation without direct epistasis experiment","pmids":["36498839"],"is_preprint":false}],"current_model":"SH3GLB2 (endophilin B2) is an N-BAR domain-containing endophilin family member that forms homo- and heterodimers with SH3GLB1 via a coiled-coil region, localizes to the cytoplasm, and positively regulates endosome maturation and trafficking—facilitating endosome acidification, EGFR degradation, autophagic flux, and viral RNA nuclear entry—while being dispensable for mitochondrial apoptosis; in vivo, loss of SH3GLB2 enhances recovery from severe influenza infection by promoting alveolar homeostasis and immune cell restoration."},"narrative":{"mechanistic_narrative":"SH3GLB2 (endophilin B2) is an N-BAR domain-containing endophilin family protein that functions as a positive regulator of endosome maturation and intracellular membrane trafficking [PMID:28455444]. It was first identified as a binding partner of endophilin B1 (SH3GLB1), forming homo- and heterodimers through a core coiled-coil region rather than its SH3 domain, and localizes to the cytoplasm where it is excluded from the nucleus [PMID:11161816]. Through its N-BAR domain-mediated control of membrane curvature, SH3GLB2 promotes endosome acidification and downstream events including EGFR degradation, autophagic flux, and influenza A viral RNA nuclear entry, while leaving endocytic internalization and lysosomal function intact [PMID:28455444]. Despite a localization and tissue distribution resembling endophilin B1 and colocalization with Bax, SH3GLB2 is dispensable for mitochondrial and Bax-mediated apoptosis [PMID:11161816, PMID:28455444]. In vivo, loss of SH3GLB2 enhances recovery from severe H1N1 influenza infection, accompanied by induction of surfactant and alveolar genes and restoration of alveolar macrophages and CD4+ lymphocytes, indicating a role in lung homeostasis and alveolar immune cell recovery [PMID:28779131].","teleology":[{"year":2001,"claim":"Established that SH3GLB2 is a cytoplasmic endophilin-family protein that dimerizes with SH3GLB1 through a defined structural element, framing it as a partner within the endophilin B system rather than an SH3-dependent adaptor.","evidence":"Yeast two-hybrid screen with domain mapping and subcellular localization","pmids":["11161816"],"confidence":"Medium","gaps":["Functional consequence of the B1–B2 dimer not addressed","No biochemical reconstitution of the coiled-coil interaction","Cellular process served by the dimer unknown"]},{"year":2001,"claim":"Tested and excluded an apoptotic role despite Bax colocalization, ruling out a direct effect of SH3GLB2 on Bax-mediated cell death.","evidence":"Overexpression in HeLa and 293T cells with apoptosis assay (negative result)","pmids":["11161816"],"confidence":"Medium","gaps":["Overexpression may not reflect endogenous function","Did not exclude apoptosis roles in other contexts"]},{"year":2017,"claim":"Defined the core cellular function of SH3GLB2 as a positive regulator of endosome maturation, linking its N-BAR membrane-curvature activity to acidification, receptor degradation, autophagy, and viral replication.","evidence":"Genetic knockout cells/mice with endosome acidification, EGFR degradation, autophagic flux, and viral RNA nuclear entry assays","pmids":["28455444"],"confidence":"High","gaps":["Direct demonstration of N-BAR membrane binding/curvature on endosomal membranes not shown","Molecular partners coupling SH3GLB2 to the acidification machinery unidentified","Whether the B1–B2 dimer mediates this function untested"]},{"year":2017,"claim":"Confirmed via genetic knockout that SH3GLB2 is dispensable for mitochondrial apoptosis, distinguishing it functionally from endophilin B1 despite shared localization.","evidence":"Genetic knockout with apoptosis assay (negative result)","pmids":["28455444"],"confidence":"Medium","gaps":["Functional divergence from endophilin B1 not mechanistically explained"]},{"year":2017,"claim":"Extended SH3GLB2 function to organismal physiology, showing that its loss improves recovery from influenza and restores alveolar homeostasis and immune cells, implicating it in lung tissue and immune recovery.","evidence":"B2-deficient mouse model with intranasal H1N1 infection, flow cytometry, gene expression analysis, and respiratory mechanics","pmids":["28779131"],"confidence":"High","gaps":["Whether the protective phenotype derives from the endosome-maturation/viral-entry role is not directly connected","Cell-type responsible for the lung phenotype not resolved"]},{"year":2022,"claim":"Placed SH3GLB2 aggregation within neurodegeneration-associated protein cascades downstream of TRAPPC6AΔ and TIAF1 in neurotoxin-treated neurons, and in AD models.","evidence":"MPP+ treatment and aggregation assays in SK-N-SH cells; 3xTg AD mouse aggregation studies","pmids":["36498839","29067327"],"confidence":"Low","gaps":["Pathway placement inferred from co-aggregation without direct epistasis","Mechanism of SH3GLB2 itself in aggregation not dissected","Causal contribution to neurodegeneration unestablished"]},{"year":null,"claim":"How SH3GLB2's N-BAR membrane-remodeling activity mechanistically drives endosome acidification, and whether its dimerization with SH3GLB1 is required for this function, remain unresolved.","evidence":"No direct biochemical or structural reconstitution in the available corpus","pmids":[],"confidence":"Low","gaps":["No structural model of SH3GLB2 on membranes","Effectors linking SH3GLB2 to V-ATPase/acidification unknown","Functional role of the B1–B2 dimer in endosome maturation untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]}],"complexes":[],"partners":["SH3GLB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NR46","full_name":"Endophilin-B2","aliases":["SH3 domain-containing GRB2-like protein B2"],"length_aa":395,"mass_kda":44.0,"function":"","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9NR46/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SH3GLB2","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000148341","cell_line_id":"CID000671","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":2}],"interactors":[{"gene":"SH3GLB1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000671","total_profiled":1310},"omim":[{"mim_id":"613270","title":"CORNEAL DYSTROPHY, FUCHS ENDOTHELIAL, 6; FECD6","url":"https://www.omim.org/entry/613270"},{"mim_id":"609288","title":"SH3 DOMAIN, GRB2-LIKE, ENDOPHILIN B2; SH3GLB2","url":"https://www.omim.org/entry/609288"},{"mim_id":"609287","title":"SH3 DOMAIN, GRB2-LIKE, ENDOPHILIN B1; SH3GLB1","url":"https://www.omim.org/entry/609287"},{"mim_id":"609141","title":"CORNEAL DYSTROPHY, POSTERIOR POLYMORPHOUS, 3; PPCD3","url":"https://www.omim.org/entry/609141"},{"mim_id":"300127","title":"OLIGOPHRENIN 1; OPHN1","url":"https://www.omim.org/entry/300127"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SH3GLB2"},"hgnc":{"alias_symbol":["KIAA1848"],"prev_symbol":[]},"alphafold":{"accession":"Q9NR46","domains":[{"cath_id":"1.20.1270.60","chopping":"35-188_207-281","consensus_level":"medium","plddt":90.8336,"start":35,"end":281},{"cath_id":"2.30.30.40","chopping":"336-395","consensus_level":"medium","plddt":88.5615,"start":336,"end":395}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NR46","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NR46-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NR46-F1-predicted_aligned_error_v6.png","plddt_mean":78.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SH3GLB2","jax_strain_url":"https://www.jax.org/strain/search?query=SH3GLB2"},"sequence":{"accession":"Q9NR46","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NR46.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NR46/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NR46"}},"corpus_meta":[{"pmid":"11161816","id":"PMC_11161816","title":"SH3GLB, a new endophilin-related protein family featuring an SH3 domain.","date":"2001","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11161816","citation_count":94,"is_preprint":false},{"pmid":"18303116","id":"PMC_18303116","title":"SPAS-1 (stimulator of prostatic adenocarcinoma-specific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockade.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18303116","citation_count":48,"is_preprint":false},{"pmid":"22127005","id":"PMC_22127005","title":"Presence of histone H3 acetylated at lysine 9 in male germ cells and its distribution pattern in the genome of human spermatozoa.","date":"2011","source":"Reproduction, fertility, and development","url":"https://pubmed.ncbi.nlm.nih.gov/22127005","citation_count":45,"is_preprint":false},{"pmid":"29067327","id":"PMC_29067327","title":"Zfra restores memory deficits in Alzheimer's disease triple-transgenic mice by blocking aggregation of TRAPPC6AΔ, SH3GLB2, tau, and amyloid β, and inflammatory NF-κB activation.","date":"2017","source":"Alzheimer's & dementia (New York, N. Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/29067327","citation_count":34,"is_preprint":false},{"pmid":"28455444","id":"PMC_28455444","title":"Endophilin B2 facilitates endosome maturation in response to growth factor stimulation, autophagy induction, and influenza A virus infection.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28455444","citation_count":29,"is_preprint":false},{"pmid":"26753958","id":"PMC_26753958","title":"Integrative proteomics and transcriptomics identify novel invasive-related biomarkers of non-functioning pituitary adenomas.","date":"2016","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26753958","citation_count":27,"is_preprint":false},{"pmid":"34359949","id":"PMC_34359949","title":"WWOX and Its Binding Proteins in Neurodegeneration.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34359949","citation_count":18,"is_preprint":false},{"pmid":"28779131","id":"PMC_28779131","title":"SH3GLB2/endophilin B2 regulates lung homeostasis and recovery from severe influenza A virus infection.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28779131","citation_count":15,"is_preprint":false},{"pmid":"32278524","id":"PMC_32278524","title":"A tumor-specific neoepitope expressed in homologous/self or heterologous/viral antigens induced comparable effector CD8+ T-cell responses by DNA vaccination.","date":"2020","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/32278524","citation_count":10,"is_preprint":false},{"pmid":"39238187","id":"PMC_39238187","title":"Multi-omics Analysis to Identify Key Immune Genes for Osteoporosis based on Machine Learning and Single-cell Analysis.","date":"2024","source":"Orthopaedic surgery","url":"https://pubmed.ncbi.nlm.nih.gov/39238187","citation_count":9,"is_preprint":false},{"pmid":"36247523","id":"PMC_36247523","title":"WGCNA combined with GSVA to explore biomarkers of refractory neocortical epilepsy.","date":"2022","source":"IBRO neuroscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/36247523","citation_count":7,"is_preprint":false},{"pmid":"36498839","id":"PMC_36498839","title":"Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36498839","citation_count":3,"is_preprint":false},{"pmid":"38542478","id":"PMC_38542478","title":"Zfra Overrides WWOX in Suppressing the Progression of Neurodegeneration.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38542478","citation_count":1,"is_preprint":false},{"pmid":"39924156","id":"PMC_39924156","title":"Predicting Diabetic Retinopathy Using a Machine Learning Approach Informed by Whole-Exome Sequencing Studies.","date":"2025","source":"Biomedical and environmental sciences : BES","url":"https://pubmed.ncbi.nlm.nih.gov/39924156","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9702,"output_tokens":1703,"usd":0.027325,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8533,"output_tokens":2336,"usd":0.050533,"stage2_stop_reason":"end_turn"},"total_usd":0.077858,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"SH3GLB2 was identified as a binding partner of SH3GLB1 in a yeast two-hybrid screen; the interaction requires a core coiled-coil-type region, while the SH3 domain is not involved in homo- or heterodimer formation. SH3GLB2 colocalizes with Bax in the cytoplasmic compartment and is excluded from the nucleus.\",\n      \"method\": \"Yeast two-hybrid screen, domain mapping, subcellular localization\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid with domain-mapping experiments and localization, single lab, two orthogonal methods\",\n      \"pmids\": [\"11161816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SH3GLB1 and SH3GLB2 do not significantly influence the onset or time course of Bax-mediated apoptosis in HeLa or 293T cells (negative result).\",\n      \"method\": \"Overexpression in HeLa and 293T cells with apoptosis assay\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay in two cell lines, single lab, negative finding explicitly reported\",\n      \"pmids\": [\"11161816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Endophilin B2 (SH3GLB2) positively regulates endosome maturation: its deficiency suppresses endosome acidification, EGFR degradation, autophagic flux, and influenza A viral RNA nuclear entry/replication, without affecting endocytic internalization or lysosomal function. The N-BAR domain is implicated in membrane curvature regulation of intracellular membrane dynamics.\",\n      \"method\": \"Genetic knockout (B2-deficient cells/mice), endosome acidification assay, EGFR degradation assay, autophagic flux assay, viral RNA nuclear entry assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional readouts in both in vitro and in vivo genetic knockout models, single lab but rigorous multi-method study\",\n      \"pmids\": [\"28455444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SH3GLB2 (endophilin B2) is dispensable for mitochondrial apoptosis despite having intracellular localization and tissue distribution similar to endophilin B1 (negative result).\",\n      \"method\": \"Genetic knockout with apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with direct apoptosis readout, single lab, explicit negative result\",\n      \"pmids\": [\"28455444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of endophilin B2 (SH3GLB2) in mice enhances recovery from severe H1N1 influenza infection, associated with induction of surfactant protein genes, ABCA3, GM-CSF, podoplanin, caveolin, CEBPα/β/δ mRNAs, restoration of alveolar macrophages, and recruitment of CD4+ lymphocytes, indicating a role for SH3GLB2 in regulating lung homeostasis and alveolar immune cell recovery.\",\n      \"method\": \"B2-deficient mouse model, intranasal H1N1 infection, flow cytometry, gene expression analysis, respiratory mechanics assessment\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic knockout with multiple orthogonal readouts (survival, immune cell profiling, gene expression, mechanics), single lab\",\n      \"pmids\": [\"28779131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SH3GLB2 protein aggregates in brain tissue of Alzheimer's disease triple-transgenic mice; Zfra peptide blocks this aggregation and restores memory, and Zfra was shown to bind cytosolic proteins to accelerate their degradation in a ubiquitin/proteasome-independent manner in vitro.\",\n      \"method\": \"In vivo 3xTg mouse model with peptide injection, in vitro aggregation assay, behavioral testing\",\n      \"journal\": \"Alzheimer's & dementia (New York, N. Y.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — SH3GLB2 aggregation observed but mechanism of SH3GLB2 itself not directly dissected; the described mechanism is for Zfra, single lab\",\n      \"pmids\": [\"29067327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SH3GLB2 aggregation occurs downstream of TRAPPC6AΔ (TPC6AΔ) and TIAF1 in a protein cascade triggered by MPP+ (a Parkinson's disease neurotoxin) in neuroblastoma SK-N-SH cells, placing SH3GLB2 in a neurodegeneration-associated aggregation pathway.\",\n      \"method\": \"Cell treatment with MPP+, protein aggregation assay in SK-N-SH neuroblastoma cells\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (aggregation assay), pathway placement inferred from co-aggregation without direct epistasis experiment\",\n      \"pmids\": [\"36498839\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3GLB2 (endophilin B2) is an N-BAR domain-containing endophilin family member that forms homo- and heterodimers with SH3GLB1 via a coiled-coil region, localizes to the cytoplasm, and positively regulates endosome maturation and trafficking—facilitating endosome acidification, EGFR degradation, autophagic flux, and viral RNA nuclear entry—while being dispensable for mitochondrial apoptosis; in vivo, loss of SH3GLB2 enhances recovery from severe influenza infection by promoting alveolar homeostasis and immune cell restoration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SH3GLB2 (endophilin B2) is an N-BAR domain-containing endophilin family protein that functions as a positive regulator of endosome maturation and intracellular membrane trafficking [#2]. It was first identified as a binding partner of endophilin B1 (SH3GLB1), forming homo- and heterodimers through a core coiled-coil region rather than its SH3 domain, and localizes to the cytoplasm where it is excluded from the nucleus [#0]. Through its N-BAR domain-mediated control of membrane curvature, SH3GLB2 promotes endosome acidification and downstream events including EGFR degradation, autophagic flux, and influenza A viral RNA nuclear entry, while leaving endocytic internalization and lysosomal function intact [#2]. Despite a localization and tissue distribution resembling endophilin B1 and colocalization with Bax, SH3GLB2 is dispensable for mitochondrial and Bax-mediated apoptosis [#1, #3]. In vivo, loss of SH3GLB2 enhances recovery from severe H1N1 influenza infection, accompanied by induction of surfactant and alveolar genes and restoration of alveolar macrophages and CD4+ lymphocytes, indicating a role in lung homeostasis and alveolar immune cell recovery [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that SH3GLB2 is a cytoplasmic endophilin-family protein that dimerizes with SH3GLB1 through a defined structural element, framing it as a partner within the endophilin B system rather than an SH3-dependent adaptor.\",\n      \"evidence\": \"Yeast two-hybrid screen with domain mapping and subcellular localization\",\n      \"pmids\": [\"11161816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the B1\\u2013B2 dimer not addressed\", \"No biochemical reconstitution of the coiled-coil interaction\", \"Cellular process served by the dimer unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Tested and excluded an apoptotic role despite Bax colocalization, ruling out a direct effect of SH3GLB2 on Bax-mediated cell death.\",\n      \"evidence\": \"Overexpression in HeLa and 293T cells with apoptosis assay (negative result)\",\n      \"pmids\": [\"11161816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression may not reflect endogenous function\", \"Did not exclude apoptosis roles in other contexts\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the core cellular function of SH3GLB2 as a positive regulator of endosome maturation, linking its N-BAR membrane-curvature activity to acidification, receptor degradation, autophagy, and viral replication.\",\n      \"evidence\": \"Genetic knockout cells/mice with endosome acidification, EGFR degradation, autophagic flux, and viral RNA nuclear entry assays\",\n      \"pmids\": [\"28455444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of N-BAR membrane binding/curvature on endosomal membranes not shown\", \"Molecular partners coupling SH3GLB2 to the acidification machinery unidentified\", \"Whether the B1\\u2013B2 dimer mediates this function untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed via genetic knockout that SH3GLB2 is dispensable for mitochondrial apoptosis, distinguishing it functionally from endophilin B1 despite shared localization.\",\n      \"evidence\": \"Genetic knockout with apoptosis assay (negative result)\",\n      \"pmids\": [\"28455444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional divergence from endophilin B1 not mechanistically explained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended SH3GLB2 function to organismal physiology, showing that its loss improves recovery from influenza and restores alveolar homeostasis and immune cells, implicating it in lung tissue and immune recovery.\",\n      \"evidence\": \"B2-deficient mouse model with intranasal H1N1 infection, flow cytometry, gene expression analysis, and respiratory mechanics\",\n      \"pmids\": [\"28779131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the protective phenotype derives from the endosome-maturation/viral-entry role is not directly connected\", \"Cell-type responsible for the lung phenotype not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed SH3GLB2 aggregation within neurodegeneration-associated protein cascades downstream of TRAPPC6A\\u0394 and TIAF1 in neurotoxin-treated neurons, and in AD models.\",\n      \"evidence\": \"MPP+ treatment and aggregation assays in SK-N-SH cells; 3xTg AD mouse aggregation studies\",\n      \"pmids\": [\"36498839\", \"29067327\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement inferred from co-aggregation without direct epistasis\", \"Mechanism of SH3GLB2 itself in aggregation not dissected\", \"Causal contribution to neurodegeneration unestablished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SH3GLB2's N-BAR membrane-remodeling activity mechanistically drives endosome acidification, and whether its dimerization with SH3GLB1 is required for this function, remain unresolved.\",\n      \"evidence\": \"No direct biochemical or structural reconstitution in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of SH3GLB2 on membranes\", \"Effectors linking SH3GLB2 to V-ATPase/acidification unknown\", \"Functional role of the B1\\u2013B2 dimer in endosome maturation untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SH3GLB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":5,"faith_pct":80.0}}