{"gene":"SH3GLB2","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2001,"finding":"SH3GLB2 (395 amino acids) was identified as an interacting partner of SH3GLB1 in a yeast two-hybrid screen. SH3GLB1 and SH3GLB2 form homo- and/or heterodimers via a core coiled-coil-type region, while the SH3 domain is not required for these interactions. Both proteins colocalize to the cytoplasmic compartment together with Bax and are excluded from the nucleus. Overexpression of SH3GLB1 or SH3GLB2 does not significantly influence Bax-mediated apoptosis in HeLa or 293T cells.","method":"Yeast two-hybrid screen, domain mapping experiments, subcellular colocalization, apoptosis functional assay","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2-3 — yeast two-hybrid with domain mapping and functional readout, single lab","pmids":["11161816"],"is_preprint":false},{"year":2017,"finding":"Endophilin B2 (SH3GLB2) positively regulates the endocytic pathway: its deficiency impairs endosome acidification, EGFR degradation, autophagic flux, and influenza A viral RNA nuclear entry and replication. The N-BAR domain-containing protein regulates trafficking of endocytic vesicles and autophagosomes to late endosomes or lysosomes, but does not affect endocytic internalization, lysosomal function, or mitochondrial apoptosis.","method":"Genetic knockout/knockdown in vitro and in vivo, endosome acidification assay, EGFR degradation assay, autophagic flux assay, viral replication assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional readouts in both in vitro and in vivo genetic models, moderate evidence","pmids":["28455444"],"is_preprint":false},{"year":2017,"finding":"SH3GLB2/endophilin B2 deficiency in mice enhanced recovery from severe influenza A (H1N1 PR8) infection, evidenced by improved survival and body weight recovery. B2-deficient lungs showed induction of surfactant proteins, ABCA3, GM-CSF, podoplanin, and caveolin mRNAs, temporal induction of CEBPα/β/δ, differences in alveolar extracellular matrix integrity and respiratory mechanics, and robust recovery of alveolar macrophages with recruitment of CD4+ lymphocytes, indicating SH3GLB2 plays a role in limiting lung homeostasis restoration after viral injury.","method":"In vivo knockout mouse model, intranasal H1N1 infection, flow cytometry, gene expression analysis, respiratory mechanics measurement","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — clean KO mouse model with multiple defined cellular and molecular phenotypic readouts","pmids":["28779131"],"is_preprint":false},{"year":2017,"finding":"SH3GLB2 aggregation occurs as part of a protein cascade (alongside TRAPPC6AΔ, tau, and amyloid β) in brains of triple-transgenic Alzheimer's disease mice. The Zfra peptide blocked SH3GLB2 aggregation in vivo, suppressed NF-κB activation, and restored memory deficits, suggesting SH3GLB2 participates in a neurodegeneration-associated aggregation pathway.","method":"In vivo peptide treatment of 3×Tg AD mice, memory testing (behavioral), immunohistochemistry, in vitro aggregation assay","journal":"Alzheimer's & dementia (New York, N. Y.)","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vivo mouse model with functional behavioral readout plus in vitro aggregation assay, single lab","pmids":["29067327"],"is_preprint":false},{"year":2022,"finding":"In neuroblastoma SK-N-SH cells treated with neurotoxin MPP+, SH3GLB2 aggregation occurs downstream of TRAPPC6AΔ and TIAF1 upregulation, and is associated with subsequent amyloid β and tau aggregation, implicating SH3GLB2 in a common protein cascade initiating both Alzheimer's and Parkinson's disease pathogenesis.","method":"Cell culture neurotoxin treatment (MPP+), immunodetection of protein aggregation, comparison with 3xTg mouse model","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single cell model, correlative aggregation measurements without direct mechanistic dissection of SH3GLB2's causal role","pmids":["36498839"],"is_preprint":false}],"current_model":"SH3GLB2 (endophilin B2) is an N-BAR domain-containing protein that forms homo- and heterodimers with SH3GLB1 via a coiled-coil region, localizes to the cytoplasm, and positively regulates endosomal trafficking—facilitating endosome maturation, EGFR degradation, autophagic flux, and viral entry—while also modulating lung inflammatory and repair responses after influenza infection; additionally, SH3GLB2 participates in a neurodegeneration-associated protein aggregation cascade involving TRAPPC6AΔ, tau, and amyloid β."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of SH3GLB2 as a dimerization partner of SH3GLB1 established that the endophilin B family members interact through a coiled-coil region rather than the SH3 domain, placing SH3GLB2 in the cytoplasmic compartment alongside Bax but without a direct role in apoptosis.","evidence":"Yeast two-hybrid screen with domain mapping, colocalization, and apoptosis assays in HeLa and 293T cells","pmids":["11161816"],"confidence":"Medium","gaps":["Interaction confirmed only by yeast two-hybrid and overexpression; endogenous complex not validated","Cellular function beyond dimerization was uncharacterized","No membrane-remodeling activity demonstrated"]},{"year":2017,"claim":"Genetic ablation revealed that SH3GLB2 is a positive regulator of endosome maturation—required for endosome acidification, EGFR degradation, and autophagic flux—thereby defining its primary cell-biological function in vesicular trafficking rather than apoptosis.","evidence":"Knockout/knockdown in vitro and in vivo with multiple orthogonal assays (endosome acidification, EGFR degradation, autophagic flux, influenza viral replication)","pmids":["28455444"],"confidence":"High","gaps":["Direct membrane-tubulating or curvature-sensing activity of the N-BAR domain was not reconstituted biochemically","Mechanism by which SH3GLB2 promotes endosome acidification is unknown","Relationship between SH3GLB1–SH3GLB2 heterodimers and endosomal function not dissected"]},{"year":2017,"claim":"SH3GLB2-deficient mice showed enhanced survival and lung repair after severe influenza infection, revealing an in vivo role for the protein in restraining alveolar epithelial restoration, surfactant production, and immune cell recruitment during post-viral recovery.","evidence":"Knockout mouse model with intranasal H1N1 infection, flow cytometry, gene expression profiling, and respiratory mechanics measurement","pmids":["28779131"],"confidence":"High","gaps":["Whether the lung phenotype is a direct consequence of impaired endosomal trafficking or involves independent signaling remains unclear","Cell-type-specific contribution of SH3GLB2 in the lung not determined","Mechanism linking SH3GLB2 to surfactant and CEBP transcription factor regulation unknown"]},{"year":2017,"claim":"SH3GLB2 was found to aggregate in brains of triple-transgenic Alzheimer's disease mice as part of a TRAPPC6AΔ–tau–amyloid β cascade, and a blocking peptide (Zfra) reversed this aggregation and memory deficits, implicating SH3GLB2 in neurodegeneration-associated protein aggregation.","evidence":"In vivo Zfra peptide treatment of 3×Tg AD mice with behavioral testing, immunohistochemistry, and in vitro aggregation assays","pmids":["29067327"],"confidence":"Medium","gaps":["Causal role of SH3GLB2 aggregation in neurodegeneration not established; evidence is correlative","Mechanism triggering SH3GLB2 aggregation undefined","Not independently replicated outside the originating group"]},{"year":null,"claim":"The biochemical basis of SH3GLB2's membrane-remodeling activity, how its N-BAR domain drives endosome maturation, and whether its aggregation is causally linked to neurodegeneration remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vitro reconstitution of N-BAR-dependent membrane remodeling for SH3GLB2","Structural basis of SH3GLB1–SH3GLB2 heterodimerization not determined","Causal link between SH3GLB2 aggregation and neuronal dysfunction not demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1]}],"complexes":[],"partners":["SH3GLB1"],"other_free_text":[]},"mechanistic_narrative":"SH3GLB2 (endophilin B2) is an N-BAR domain-containing protein that forms homo- and heterodimers with SH3GLB1 via a coiled-coil region and positively regulates endosomal trafficking [PMID:11161816, PMID:28455444]. Its deficiency impairs endosome acidification, EGFR degradation, and autophagic flux without affecting endocytic internalization or lysosomal function, and it facilitates influenza A viral RNA nuclear entry by promoting endocytic vesicle maturation [PMID:28455444]. In vivo, SH3GLB2 knockout enhances lung recovery after influenza infection by restoring surfactant expression, alveolar macrophage populations, and extracellular matrix integrity, indicating a role in restraining tissue repair responses [PMID:28779131]. SH3GLB2 also aggregates as part of a TRAPPC6AΔ–TIAF1–tau–amyloid β protein cascade in Alzheimer's disease mouse models [PMID:29067327]."},"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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":44,"is_preprint":false,"source_track":"pubmed_title"},{"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. 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SH3GLB2 colocalizes with Bax in the cytoplasmic compartment and is excluded from the nucleus.\",\n      \"method\": \"Yeast two-hybrid screen, yeast two-hybrid domain mapping, subcellular localization (colocalization imaging), functional apoptosis assays in HeLa/293T cells\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — yeast two-hybrid with domain mapping and localization; single lab, moderate orthogonal methods\",\n      \"pmids\": [\"11161816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Endophilin B2 (SH3GLB2) regulates endosomal trafficking via its N-BAR domain-mediated membrane curvature activity; loss of endophilin B2 impairs endosome acidification, EGFR degradation, autophagic flux, and influenza A viral RNA nuclear entry without affecting endocytic internalization or lysosomal function. Endophilin B2 is dispensable for mitochondrial apoptosis.\",\n      \"method\": \"Genetic knockout (endophilin B2-deficient mice/cells), endosome acidification assays, EGFR degradation assays, autophagic flux assays, viral replication assays, subcellular fractionation/trafficking experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined cellular phenotypes and pathway placement, orthogonal functional readouts\",\n      \"pmids\": [\"28455444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SH3GLB2/endophilin B2 deficiency in mice enhances recovery from severe influenza A infection, associated with induction of surfactant proteins, ABCA3, GM-CSF, podoplanin, and caveolin mRNAs, CEBPα/β/δ induction, and robust recovery of alveolar macrophages and CD4+ lymphocyte recruitment, indicating endophilin B2 negatively regulates lung homeostasis and alveolar immune recovery.\",\n      \"method\": \"Genetic knockout mice (B2-deficient), survival studies, flow cytometry, gene expression analysis, respiratory mechanics measurements\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined phenotypic readouts in vivo; single lab\",\n      \"pmids\": [\"28779131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SH3GLB2 aggregation participates in a protein cascade (alongside TRAPPC6AΔ, TIAF1, tau, and amyloid β) downstream of WWOX downregulation, contributing to neurodegeneration; Zfra peptide blocks SH3GLB2 aggregation and suppresses NF-κB-mediated inflammation, restoring memory in 3×Tg AD mice.\",\n      \"method\": \"In vivo peptide treatment (Zfra tail vein injection) in triple-transgenic AD mice, in vitro aggregation blocking assays, behavioral memory tests (Morris water maze), protein aggregate quantification\",\n      \"journal\": \"Alzheimer's & dementia (New York, N. Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — in vivo rescue with defined molecular readouts; pathway placement supported by multiple methods but single lab\",\n      \"pmids\": [\"29067327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SH3GLB2 aggregation is downstream of TRAPPC6AΔ (TPC6AΔ) and TIAF1 in a neurodegeneration cascade triggered by WWOX downregulation; in neuroblastoma SK-N-SH cells treated with neurotoxin MPP+, TPC6AΔ upregulation and aggregation drives co-aggregation of TIAF1, SH3GLB2, amyloid β, and tau, identifying TPC6AΔ as an upstream initiator.\",\n      \"method\": \"Cell-based neurotoxin (MPP+) treatment, protein aggregation assays, Zfra peptide intervention in 3xTg mice, novel object recognition and Morris water maze behavioral assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pathway placement by cell-based assay and in vivo rescue, but single lab and limited mechanistic resolution for SH3GLB2 specifically\",\n      \"pmids\": [\"36498839\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3GLB2 (endophilin B2) is an N-BAR domain-containing endophilin family protein that forms homo- and heterodimers with SH3GLB1 via a coiled-coil region, localizes to the cytoplasm, and positively regulates endosomal maturation and trafficking (promoting endosome acidification, EGFR degradation, autophagic flux, and viral endosomal escape) while being dispensable for mitochondrial apoptosis; additionally, SH3GLB2 participates in a neurodegeneration-associated protein aggregation cascade downstream of TRAPPC6AΔ and WWOX loss, and negatively regulates alveolar immune recovery during severe influenza infection.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"SH3GLB2 (395 amino acids) was identified as an interacting partner of SH3GLB1 in a yeast two-hybrid screen. SH3GLB1 and SH3GLB2 form homo- and/or heterodimers via a core coiled-coil-type region, while the SH3 domain is not required for these interactions. Both proteins colocalize to the cytoplasmic compartment together with Bax and are excluded from the nucleus. Overexpression of SH3GLB1 or SH3GLB2 does not significantly influence Bax-mediated apoptosis in HeLa or 293T cells.\",\n      \"method\": \"Yeast two-hybrid screen, domain mapping experiments, subcellular colocalization, apoptosis functional assay\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — yeast two-hybrid with domain mapping and functional readout, single lab\",\n      \"pmids\": [\"11161816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Endophilin B2 (SH3GLB2) positively regulates the endocytic pathway: its deficiency impairs endosome acidification, EGFR degradation, autophagic flux, and influenza A viral RNA nuclear entry and replication. The N-BAR domain-containing protein regulates trafficking of endocytic vesicles and autophagosomes to late endosomes or lysosomes, but does not affect endocytic internalization, lysosomal function, or mitochondrial apoptosis.\",\n      \"method\": \"Genetic knockout/knockdown in vitro and in vivo, endosome acidification assay, EGFR degradation assay, autophagic flux assay, viral replication assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional readouts in both in vitro and in vivo genetic models, moderate evidence\",\n      \"pmids\": [\"28455444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SH3GLB2/endophilin B2 deficiency in mice enhanced recovery from severe influenza A (H1N1 PR8) infection, evidenced by improved survival and body weight recovery. B2-deficient lungs showed induction of surfactant proteins, ABCA3, GM-CSF, podoplanin, and caveolin mRNAs, temporal induction of CEBPα/β/δ, differences in alveolar extracellular matrix integrity and respiratory mechanics, and robust recovery of alveolar macrophages with recruitment of CD4+ lymphocytes, indicating SH3GLB2 plays a role in limiting lung homeostasis restoration after viral injury.\",\n      \"method\": \"In vivo knockout mouse model, intranasal H1N1 infection, flow cytometry, gene expression analysis, respiratory mechanics measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO mouse model with multiple defined cellular and molecular phenotypic readouts\",\n      \"pmids\": [\"28779131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SH3GLB2 aggregation occurs as part of a protein cascade (alongside TRAPPC6AΔ, tau, and amyloid β) in brains of triple-transgenic Alzheimer's disease mice. The Zfra peptide blocked SH3GLB2 aggregation in vivo, suppressed NF-κB activation, and restored memory deficits, suggesting SH3GLB2 participates in a neurodegeneration-associated aggregation pathway.\",\n      \"method\": \"In vivo peptide treatment of 3×Tg AD mice, memory testing (behavioral), immunohistochemistry, in vitro aggregation assay\",\n      \"journal\": \"Alzheimer's & dementia (New York, N. Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo mouse model with functional behavioral readout plus in vitro aggregation assay, single lab\",\n      \"pmids\": [\"29067327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In neuroblastoma SK-N-SH cells treated with neurotoxin MPP+, SH3GLB2 aggregation occurs downstream of TRAPPC6AΔ and TIAF1 upregulation, and is associated with subsequent amyloid β and tau aggregation, implicating SH3GLB2 in a common protein cascade initiating both Alzheimer's and Parkinson's disease pathogenesis.\",\n      \"method\": \"Cell culture neurotoxin treatment (MPP+), immunodetection of protein aggregation, comparison with 3xTg mouse model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single cell model, correlative aggregation measurements without direct mechanistic dissection of SH3GLB2's causal role\",\n      \"pmids\": [\"36498839\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SH3GLB2 (endophilin B2) is an N-BAR domain-containing protein that forms homo- and heterodimers with SH3GLB1 via a coiled-coil region, localizes to the cytoplasm, and positively regulates endosomal trafficking—facilitating endosome maturation, EGFR degradation, autophagic flux, and viral entry—while also modulating lung inflammatory and repair responses after influenza infection; additionally, SH3GLB2 participates in a neurodegeneration-associated protein aggregation cascade involving TRAPPC6AΔ, tau, and amyloid β.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SH3GLB2 (endophilin B2) is an N-BAR domain-containing protein that forms homo- and heterodimers with SH3GLB1 via a coiled-coil region and functions as a positive regulator of endosomal maturation and trafficking [PMID:11161816, PMID:28455444]. Loss of SH3GLB2 impairs endosome acidification, EGFR degradation, autophagic flux, and influenza A viral RNA nuclear entry without affecting endocytic internalization, lysosomal function, or mitochondrial apoptosis, establishing its role specifically at the endosome maturation step [PMID:28455444]. In vivo, SH3GLB2 deficiency enhances alveolar immune recovery and macrophage reconstitution following severe influenza infection, indicating a negative regulatory role in lung homeostasis [PMID:28779131]. SH3GLB2 also participates in a protein aggregation cascade downstream of WWOX loss and TRAPPC6AΔ, contributing to tau and amyloid β co-aggregation in neurodegeneration models [PMID:29067327, PMID:36498839].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identifying SH3GLB2 as a dimerization partner of SH3GLB1 established the endophilin B family as a heterodimer-forming unit and mapped the coiled-coil region as the required interaction domain, while excluding the SH3 domain from this role.\",\n      \"evidence\": \"Yeast two-hybrid screen with domain-deletion mapping and colocalization imaging in HeLa/293T cells\",\n      \"pmids\": [\"11161816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No biochemical validation of the dimer (e.g., co-immunoprecipitation or biophysical binding assay) beyond yeast two-hybrid\",\n        \"Functional consequence of SH3GLB1–SH3GLB2 heterodimerization was not tested\",\n        \"SH3 domain ligands for SH3GLB2 were not identified\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic knockout of SH3GLB2 revealed its essential and specific role in endosome maturation — not internalization or lysosomal function — by demonstrating impaired endosome acidification, delayed EGFR degradation, reduced autophagic flux, and blocked influenza viral escape, while ruling out a requirement in mitochondrial apoptosis.\",\n      \"evidence\": \"Endophilin B2-deficient mice and derived cells with acidification, EGFR degradation, autophagy, and viral replication assays\",\n      \"pmids\": [\"28455444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of N-BAR domain membrane remodeling at endosomes is unresolved\",\n        \"Whether SH3GLB1 compensates partially in the knockout is not addressed\",\n        \"Direct protein targets or effectors recruited by SH3GLB2 at endosomes remain unidentified\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"In vivo knockout studies demonstrated that SH3GLB2 negatively regulates alveolar immune recovery during severe influenza infection, linking its endosomal trafficking function to tissue-level immune homeostasis in the lung.\",\n      \"evidence\": \"SH3GLB2-deficient mice subjected to influenza infection with survival, flow cytometry, gene expression, and respiratory mechanics analyses\",\n      \"pmids\": [\"28779131\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the protective phenotype is cell-intrinsic to macrophages or epithelial cells was not determined\",\n        \"Mechanism connecting impaired endosomal maturation to enhanced immune recovery is unclear\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"SH3GLB2 was placed within a protein aggregation cascade downstream of WWOX loss, where it co-aggregates with TIAF1, tau, and amyloid β, linking an endosomal trafficking protein to neurodegeneration pathology.\",\n      \"evidence\": \"Zfra peptide intervention in 3×Tg AD mice with aggregation blocking assays and Morris water maze behavioral tests\",\n      \"pmids\": [\"29067327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SH3GLB2 aggregation is causative or a bystander in neurodegeneration is not resolved\",\n        \"Direct interaction between SH3GLB2 and tau or amyloid β was not demonstrated biochemically\",\n        \"Single-lab observation\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"TRAPPC6AΔ was identified as an upstream initiator that drives SH3GLB2 co-aggregation with TIAF1 and tau upon neurotoxin exposure, refining the cascade hierarchy.\",\n      \"evidence\": \"MPP+-treated SK-N-SH neuroblastoma cells with protein aggregation assays and Zfra rescue in 3×Tg mice\",\n      \"pmids\": [\"36498839\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Mechanistic resolution for SH3GLB2 specifically is limited — aggregation is observed but not causally dissected\",\n        \"Single-lab study without independent confirmation\",\n        \"No structural or biophysical characterization of SH3GLB2 aggregates\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular effectors recruited by SH3GLB2 at endosomal membranes, the structural basis of its N-BAR domain activity in endosome maturation, and whether its aggregation in neurodegeneration reflects a loss-of-endosomal-function mechanism all remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No interactome beyond SH3GLB1 has been mapped\",\n        \"No crystal or cryo-EM structure of SH3GLB2\",\n        \"Relationship between endosomal trafficking defects and protein aggregation phenotype is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SH3GLB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"SH3GLB2 (endophilin B2) is an N-BAR domain-containing protein that forms homo- and heterodimers with SH3GLB1 via a coiled-coil region and positively regulates endosomal trafficking [PMID:11161816, PMID:28455444]. Its deficiency impairs endosome acidification, EGFR degradation, and autophagic flux without affecting endocytic internalization or lysosomal function, and it facilitates influenza A viral RNA nuclear entry by promoting endocytic vesicle maturation [PMID:28455444]. In vivo, SH3GLB2 knockout enhances lung recovery after influenza infection by restoring surfactant expression, alveolar macrophage populations, and extracellular matrix integrity, indicating a role in restraining tissue repair responses [PMID:28779131]. SH3GLB2 also aggregates as part of a TRAPPC6AΔ–TIAF1–tau–amyloid β protein cascade in Alzheimer's disease mouse models [PMID:29067327].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of SH3GLB2 as a dimerization partner of SH3GLB1 established that the endophilin B family members interact through a coiled-coil region rather than the SH3 domain, placing SH3GLB2 in the cytoplasmic compartment alongside Bax but without a direct role in apoptosis.\",\n      \"evidence\": \"Yeast two-hybrid screen with domain mapping, colocalization, and apoptosis assays in HeLa and 293T cells\",\n      \"pmids\": [\"11161816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction confirmed only by yeast two-hybrid and overexpression; endogenous complex not validated\",\n        \"Cellular function beyond dimerization was uncharacterized\",\n        \"No membrane-remodeling activity demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic ablation revealed that SH3GLB2 is a positive regulator of endosome maturation—required for endosome acidification, EGFR degradation, and autophagic flux—thereby defining its primary cell-biological function in vesicular trafficking rather than apoptosis.\",\n      \"evidence\": \"Knockout/knockdown in vitro and in vivo with multiple orthogonal assays (endosome acidification, EGFR degradation, autophagic flux, influenza viral replication)\",\n      \"pmids\": [\"28455444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct membrane-tubulating or curvature-sensing activity of the N-BAR domain was not reconstituted biochemically\",\n        \"Mechanism by which SH3GLB2 promotes endosome acidification is unknown\",\n        \"Relationship between SH3GLB1–SH3GLB2 heterodimers and endosomal function not dissected\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"SH3GLB2-deficient mice showed enhanced survival and lung repair after severe influenza infection, revealing an in vivo role for the protein in restraining alveolar epithelial restoration, surfactant production, and immune cell recruitment during post-viral recovery.\",\n      \"evidence\": \"Knockout mouse model with intranasal H1N1 infection, flow cytometry, gene expression profiling, and respiratory mechanics measurement\",\n      \"pmids\": [\"28779131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the lung phenotype is a direct consequence of impaired endosomal trafficking or involves independent signaling remains unclear\",\n        \"Cell-type-specific contribution of SH3GLB2 in the lung not determined\",\n        \"Mechanism linking SH3GLB2 to surfactant and CEBP transcription factor regulation unknown\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"SH3GLB2 was found to aggregate in brains of triple-transgenic Alzheimer's disease mice as part of a TRAPPC6AΔ–tau–amyloid β cascade, and a blocking peptide (Zfra) reversed this aggregation and memory deficits, implicating SH3GLB2 in neurodegeneration-associated protein aggregation.\",\n      \"evidence\": \"In vivo Zfra peptide treatment of 3×Tg AD mice with behavioral testing, immunohistochemistry, and in vitro aggregation assays\",\n      \"pmids\": [\"29067327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Causal role of SH3GLB2 aggregation in neurodegeneration not established; evidence is correlative\",\n        \"Mechanism triggering SH3GLB2 aggregation undefined\",\n        \"Not independently replicated outside the originating group\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical basis of SH3GLB2's membrane-remodeling activity, how its N-BAR domain drives endosome maturation, and whether its aggregation is causally linked to neurodegeneration remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in vitro reconstitution of N-BAR-dependent membrane remodeling for SH3GLB2\",\n        \"Structural basis of SH3GLB1–SH3GLB2 heterodimerization not determined\",\n        \"Causal link between SH3GLB2 aggregation and neuronal dysfunction not demonstrated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SH3GLB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}