Affinage

SH3GLB2

Endophilin-B2 · UniProt Q9NR46

Round 2 corrected
Length
395 aa
Mass
44.0 kDa
Annotated
2026-04-28
44 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2001 Medium

    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

    PMID:11161816

    Open questions at the time
    • Interaction confirmed only by yeast two-hybrid and overexpression; endogenous complex not validated
    • Cellular function beyond dimerization was uncharacterized
    • No membrane-remodeling activity demonstrated
  2. 2017 High

    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)

    PMID:28455444

    Open questions at the time
    • 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
  3. 2017 High

    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

    PMID:28779131

    Open questions at the time
    • 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
  4. 2017 Medium

    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

    PMID:29067327

    Open questions at the time
    • Causal role of SH3GLB2 aggregation in neurodegeneration not established; evidence is correlative
    • Mechanism triggering SH3GLB2 aggregation undefined
    • Not independently replicated outside the originating group

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 1
Localization
GO:0005829 cytosol 2 GO:0005768 endosome 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 1 R-HSA-9612973 Autophagy 1
Partners
SH3GLB1

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 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. Yeast two-hybrid screen, domain mapping experiments, subcellular colocalization, apoptosis functional assay Genomics Medium 11161816
2017 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. Genetic knockout/knockdown in vitro and in vivo, endosome acidification assay, EGFR degradation assay, autophagic flux assay, viral replication assay The Journal of biological chemistry High 28455444
2017 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. In vivo knockout mouse model, intranasal H1N1 infection, flow cytometry, gene expression analysis, respiratory mechanics measurement Scientific reports High 28779131
2017 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. In vivo peptide treatment of 3×Tg AD mice, memory testing (behavioral), immunohistochemistry, in vitro aggregation assay Alzheimer's & dementia (New York, N. Y.) Medium 29067327
2022 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. Cell culture neurotoxin treatment (MPP+), immunodetection of protein aggregation, comparison with 3xTg mouse model International journal of molecular sciences Low 36498839

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Network organization of the human autophagy system. Nature 1286 20562859
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2002 Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature 471 11894095
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2013 Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions. Science signaling 383 24255178
2002 The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met. Nature 371 11894096
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2022 Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell 256 35063084
2014 Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. Journal of proteomics 215 25281560
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2011 Protein interactome reveals converging molecular pathways among autism disorders. Science translational medicine 180 21653829
2014 E-cadherin interactome complexity and robustness resolved by quantitative proteomics. Science signaling 162 25468996
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2018 Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains. Molecular cell 136 30554943
2001 Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 123 11347906
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2021 Protein interaction landscapes revealed by advanced in vivo cross-linking-mass spectrometry. Proceedings of the National Academy of Sciences of the United States of America 113 34349018
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2017 Mammalian APE1 controls miRNA processing and its interactome is linked to cancer RNA metabolism. Nature communications 99 28986522
2001 SH3GLB, a new endophilin-related protein family featuring an SH3 domain. Genomics 94 11161816
2008 SPAS-1 (stimulator of prostatic adenocarcinoma-specific T cells)/SH3GLB2: A prostate tumor antigen identified by CTLA-4 blockade. Proceedings of the National Academy of Sciences of the United States of America 48 18303116
2011 Presence of histone H3 acetylated at lysine 9 in male germ cells and its distribution pattern in the genome of human spermatozoa. Reproduction, fertility, and development 44 22127005
2017 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. Alzheimer's & dementia (New York, N. Y.) 32 29067327
2017 Endophilin B2 facilitates endosome maturation in response to growth factor stimulation, autophagy induction, and influenza A virus infection. The Journal of biological chemistry 29 28455444
2016 Integrative proteomics and transcriptomics identify novel invasive-related biomarkers of non-functioning pituitary adenomas. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 27 26753958
2021 WWOX and Its Binding Proteins in Neurodegeneration. Cells 18 34359949
2017 SH3GLB2/endophilin B2 regulates lung homeostasis and recovery from severe influenza A virus infection. Scientific reports 15 28779131
2020 A tumor-specific neoepitope expressed in homologous/self or heterologous/viral antigens induced comparable effector CD8+ T-cell responses by DNA vaccination. Vaccine 10 32278524
2024 Multi-omics Analysis to Identify Key Immune Genes for Osteoporosis based on Machine Learning and Single-cell Analysis. Orthopaedic surgery 7 39238187
2022 WGCNA combined with GSVA to explore biomarkers of refractory neocortical epilepsy. IBRO neuroscience reports 6 36247523
2022 Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration. International journal of molecular sciences 3 36498839
2024 Zfra Overrides WWOX in Suppressing the Progression of Neurodegeneration. International journal of molecular sciences 1 38542478
2025 Predicting Diabetic Retinopathy Using a Machine Learning Approach Informed by Whole-Exome Sequencing Studies. Biomedical and environmental sciences : BES 0 39924156