Affinage

APBA3

Amyloid-beta A4 precursor protein-binding family A member 3 · UniProt O96018

Length
575 aa
Mass
61.5 kDa
Annotated
2026-06-09
27 papers in source corpus 19 papers cited in narrative 19 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

APBA3/Mint3 (X11L2) is a multifunctional Golgi-associated adaptor protein that couples vesicular trafficking decisions to metabolic and immune signaling (PMID:19726677, PMID:17959829). Through its PTB domain it binds the intracellular YENPTY motif of APP via Tyr-682, marking APP-containing vesicles for export from the trans-Golgi network along the basolateral/cell-surface route rather than the endosomal/lysosomal route, thereby suppressing amyloidogenic Aβ generation (PMID:10049767, PMID:17959829, PMID:23965993); this Golgi trafficking activity is linked to GTP-loaded Rab6A, which binds the complete PTB domain and co-localizes with Mint3 and APP at Golgi membranes (PMID:16207088, PMID:20447381). Its tandem PDZ domains direct other cargoes, retrieving internalized MT5-MMP to the plasma membrane via its C-terminal EWV motif and retaining Furin at the TGN (PMID:14990567, PMID:18544638). In parallel, the intrinsically disordered N-terminal region of Mint3 (core residues 78–88) directly binds and constitutively inhibits FIH-1 in an oxygen-independent manner through a coupled folding-and-binding mechanism, blocking FIH-1-mediated hydroxylation of HIF-1α Asn803 and sustaining normoxic HIF-1 transcriptional activity to drive Warburg-type glycolytic ATP production (PMID:19726677, PMID:34655613). Genetic deletion in mice establishes this FIH-1–HIF-1 axis as the basis of a cell-type-specific role in macrophage energy metabolism, with knockout animals showing reduced glycolysis, cytokine production, and resistance to LPS-induced septic shock (PMID:21778228). This glycolytic program supports inflammatory monocyte chemotaxis and VEGFA-driven endothelial E-selectin expression that promotes cancer cell extravasation and metastasis (PMID:28507122), and in tumor cells the Mint3–HIF-1 axis sustains proliferation through SKP2 induction and protects against chemotherapy-induced energy stress (PMID:32826949, PMID:38081808). Independently of metabolism, Mint3 promotes K63-linked polyubiquitination of TRAF3 and STING to enhance IRF3 activation and type I IFN antiviral responses (PMID:27698125, PMID:40254147).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1999 Medium

    Established APBA3 as a direct binding partner of APP, defining its candidate role in APP biology before any trafficking function was known.

    Evidence GST pull-down and reciprocal Co-IP of the PTB domain with the APP intracellular domain

    PMID:10049767

    Open questions at the time
    • Functional consequence of the interaction not addressed
    • Domain mapping to specific APP motifs not yet resolved
  2. 2004 High

    Showed the PDZ domains can engage cargo independent of the PTB/APP axis, expanding Mint3 to a multi-cargo adaptor that controls surface recycling.

    Evidence Yeast two-hybrid, EWV motif deletion, and siRNA knockdown measuring MT5-MMP surface activity; separate PDZ binding/co-localization for Bcr

    PMID:14990567 PMID:15494376

    Open questions at the time
    • Bcr interaction is Low-confidence with no functional follow-up
    • How PDZ cargo selection is coordinated with PTB cargo unknown
  3. 2005 Medium

    Linked Mint3 to a small GTPase regulator of Golgi trafficking, providing a mechanism for how APP vesicles are organized at the Golgi.

    Evidence Yeast two-hybrid, GTP-dependency assay, confocal co-localization of Rab6A/Mint3/APP, later confirmed by live-cell FRET with PTB-domain mutants

    PMID:16207088 PMID:20447381

    Open questions at the time
    • No reciprocal Co-IP in mammalian cells in original report
    • Directionality of Rab6A regulation of Mint3 versus the reverse not established
  4. 2007 High

    Defined Mint3 as a determinant of post-Golgi APP sorting fate, mechanistically tying the adaptor to amyloidogenic processing.

    Evidence APP-vesicle purification, siRNA knockdown rerouting APP, and Aβ(1-40) ELISA; parallel work mapped nucleo-cytoplasmic shuttling and a transcriptional activator activity

    PMID:17959829 PMID:18201694

    Open questions at the time
    • Mechanism connecting the nuclear shuttling/transcriptional activity to cytoplasmic trafficking roles unclear
    • Endogenous transcriptional targets of nuclear Mint3 not identified
  5. 2008 Medium

    Generalized Mint3's PTB-domain adaptor function to TGN retention of Furin, showing it organizes the localization of multiple secretory-pathway proteins.

    Evidence Co-IP, immunofluorescence, siRNA knockdown with Furin redistribution, and domain mapping in HeLa cells

    PMID:18544638

    Open questions at the time
    • Whether Furin and APP compete for the same PTB site unknown
    • Physiological consequence of Furin mislocalization not measured
  6. 2009 High

    Identified a metabolic function entirely separate from trafficking: constitutive, oxygen-independent inhibition of FIH-1 to sustain normoxic HIF-1 activity and glycolysis.

    Evidence Purified-protein FIH-1 inhibition assay, HIF-1 reporter, siRNA knockdown, and biochemical fractionation in macrophages

    PMID:19726677

    Open questions at the time
    • Whether the same molecule performs trafficking and FIH-1 inhibition simultaneously unresolved
    • Structural basis of FIH-1 binding not yet defined at this stage
  7. 2011 High

    Validated the FIH-1–HIF-1 axis in vivo and assigned it a cell-type-specific role in macrophage energetics and inflammation.

    Evidence Germline and myeloid-specific Apba3 knockout mice with ATP, glycolysis, cytokine readouts and an LPS septic shock model

    PMID:21778228

    Open questions at the time
    • Contribution of trafficking functions to the in vivo phenotype not dissected
    • Non-myeloid roles of the axis untested here
  8. 2013 Medium

    Pinpointed the APP motif and residue (Tyr-682) that recruits Mint3 to the Golgi for APP export, refining the trafficking mechanism.

    Evidence Systematic site-directed mutagenesis of APP sorting motifs and subcellular localization assays

    PMID:23965993

    Open questions at the time
    • LAMP1+ destination characterization incomplete
    • Single-lab finding
  9. 2014 Medium

    Demonstrated cell-type dependence of the FIH-1–Mint3 axis, showing it does not govern endogenous HIF-1 activity in all tissues.

    Evidence HIF-1 reporter with Mint3 N-terminus domain mapping and microarray after FIH-1 silencing in nucleus pulposus cells

    PMID:24867948

    Open questions at the time
    • Reason for cell-type specificity of the axis unexplained
    • Negative endogenous result based on transcript profiling only
  10. 2016 Medium

    Uncovered a ubiquitin-dependent immune signaling role, expanding Mint3 from metabolism into antiviral and inflammatory signaling.

    Evidence Mint3 KO/knockdown macrophages with K63-polyubiquitination assays on TRAF3, IRF3/IFN-β readouts, and NF-κB/AMPK pathway analysis in influenza models

    PMID:27698125 PMID:27883071

    Open questions at the time
    • How Mint3 promotes K63 ubiquitination mechanistically (E3 partner) unknown
    • Relationship between immune signaling and metabolic functions of Mint3 unclear
  11. 2017 High

    Connected the macrophage glycolytic program to pathophysiology, showing host Mint3 drives metastatic niche formation.

    Evidence APBA3 KO mice, bone marrow transplant, chemotaxis assays, VEGFA/E-selectin measurement and E-selectin neutralizing-antibody rescue in metastasis models

    PMID:28507122

    Open questions at the time
    • Whether tumor-cell-intrinsic Mint3 contributes alongside host Mint3 not fully separated here
  12. 2021 High

    Provided the structural mechanism for FIH-1 inhibition, defining a disorder-to-order coupled folding-and-binding core at residues 78–88.

    Evidence CD, NMR, HDX-MS and ITC with truncation mutants

    PMID:34655613

    Open questions at the time
    • No co-crystal/complex structure of the bound state
    • How binding sterically blocks FIH-1 catalysis not directly visualized
  13. 2023 Medium

    Extended the Mint3–HIF-1 glycolytic axis to tumor-cell-intrinsic survival, linking it to AMPK/mTOR/HSF1 stress responses and chemoresistance.

    Evidence shRNA depletion, transcriptome and AMPK/mTOR/HSP70 pathway analysis in TNBC in vivo models; parallel SKP2 axis in pancreatic cancer

    PMID:32826949 PMID:38081808

    Open questions at the time
    • Direct versus indirect effects on HSF1/SKP2 not fully separated
    • Single-lab tumor models
  14. 2025 Medium

    Added STING to the Mint3 ubiquitination/trafficking repertoire, unifying its trafficking and immune-signaling roles in cytosolic DNA sensing.

    Evidence Co-IP, K63-polyubiquitination assay, STING ER-to-Golgi translocation and TBK1 interaction assays, KO macrophages and in vivo HSV-1 challenge

    PMID:40254147

    Open questions at the time
    • Not independently replicated
    • Whether Golgi-trafficking machinery (Rab6A) participates in STING relocation untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single adaptor partitions between its Golgi-trafficking, FIH-1/HIF-1 metabolic, and ubiquitin-dependent immune functions—and how these are coordinated within one cell—remains unresolved.
  • No integrated model linking PTB/PDZ trafficking to N-terminal FIH-1 inhibition
  • E3 ligase mediating Mint3-dependent K63 ubiquitination unidentified
  • Structure of Mint3 in complex with any partner unsolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005794 Golgi apparatus 5 GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-9609507 Protein localization 4 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-162582 Signal Transduction 2
Partners
APPBCRFIH1FURINMMP24RAB6ASTING1TRAF3

Evidence

Reading pass · 19 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 APBA3/X11L2 PID/PTB domain directly interacts with the intracellular domain of APP (amyloid precursor protein), as demonstrated by GST binding assay in vitro and confirmed by co-immunoprecipitation from cells overexpressing APP and HA-tagged X11L2. GST pull-down assay, co-immunoprecipitation Biochemical and biophysical research communications Medium 10049767
2009 Mint3/APBA3 binds directly to FIH-1 (factor inhibiting HIF-1) and inhibits FIH-1's ability to hydroxylate HIF-1α Asn803, thereby preventing FIH-1-mediated suppression of HIF-1 transcriptional activity in an oxygen-independent manner. In macrophages, this mechanism sustains HIF-1 activity during normoxia and supports glycolytic ATP production. Knockdown of Mint3 redistributes FIH-1 from the perinuclear region to the cytoplasm and decreases glycolysis and ATP production. Purified protein binding assay (in vitro), HIF-1 reporter assay, siRNA knockdown, immunofluorescence co-localization, biochemical fractionation The Journal of biological chemistry High 19726677
2007 Mint3 is specifically enriched in APP-containing vesicles purified from neuroblastoma cells, and depletion of Mint3 by siRNA redirects APP export from the basolateral/trans-Golgi route to the endosomal/lysosomal route; Mint3 overexpression decreases and siRNA knockdown increases Aβ(1-40) secretion, identifying Mint3 as a critical determinant of post-Golgi APP trafficking. Vesicle purification from cells, siRNA knockdown, subcellular localization/trafficking assay, Aβ ELISA Molecular biology of the cell High 17959829
2004 The PDZ domains of Mint-3 bind the carboxyl EWV motif of MT5-MMP (identified by yeast two-hybrid screening), and this interaction mediates retrieval of internalized MT5-MMP to the plasma membrane; deletion of EWV impairs recycling without affecting internalization, and siRNA-mediated knockdown of Mint-3 decreases MT5-MMP surface activity. Yeast two-hybrid, siRNA knockdown, cell surface activity assay, deletion mutagenesis The Journal of biological chemistry High 14990567
2005 Rab6A GTPase interacts with Mint3 in a GTP-dependent manner, requiring the complete PTB domain of Mint3. Rab6A, Mint3, and APP co-localize at Golgi membranes in HeLa cells, suggesting Mint3 links Rab6A to APP trafficking. Yeast two-hybrid, confocal microscopy co-localization, density gradient centrifugation, GTP-dependency assay Biological chemistry Medium 16207088
2008 Mint3 PTB domain interacts with the acidic peptide signal of Furin in HeLa cells (shown by co-immunoprecipitation and immunofluorescence), and Mint3 knockdown by RNAi disrupts TGN-specific localization of Furin, redistributing it to endosomes. Co-immunoprecipitation, immunofluorescence, siRNA knockdown, domain mapping/mutagenesis Journal of cell science Medium 18544638
2013 Mint3 is recruited to the Golgi by the YENPTY motif of APP specifically via Tyr-682, and this recruitment is required for APP export from the Golgi; after leaving the Golgi, APP is directed to LAMP1+ structures as the proximal destination. Site-directed mutagenesis of APP sorting motifs, subcellular localization assay, adaptor recruitment assay The Journal of biological chemistry Medium 23965993
2011 Genetic deletion of Apba3 in mice reduces ATP production in macrophages to ~60% of wild-type, decreases glycolysis, cytokine production, and motility, and confers resistance to LPS-induced septic shock; myeloid-specific deletion recapitulates the septic shock resistance, establishing a cell-type-specific role for APBA3 in macrophage energy metabolism via the FIH-1–HIF-1 pathway. Apba3 knockout mice, myeloid-specific conditional knockout, ATP measurement, cytokine assay, LPS-induced septic shock model The Journal of biological chemistry High 21778228
2007 X11L2/APBA3 shuttles between the cytoplasm and nucleus via a nuclear export signal (NES) in its N-terminus; mutation of the NES causes nuclear accumulation, and X11L2 tethered near a promoter (via Gal4-DBD fusion) displays transcriptional activator activity, which is attenuated by preventing nucleo-cytoplasmic shuttling. Leptomycin B treatment, FLIP (fluorescence loss in photobleaching), NES mutagenesis, Gal4-DBD transcription reporter assay, nuclear fractionation Experimental cell research Medium 18201694
2004 The C-terminal PDZ-binding motif of Bcr (breakpoint cluster region protein) specifically binds to the PDZ domains of Mint3, localizing Bcr to the Golgi compartment where Mint3 resides. PDZ domain binding assay, co-localization immunofluorescence Journal of cell science Low 15494376
2010 The PTB domain of Mint3 (Mint3Δ6) is sufficient to interact with constitutively active (GTP-loaded) Rab6A in living mammalian cells, as confirmed by FACS-based FRET analysis; a mutant lacking part of the PTB domain (Mint3Δ4) fails to interact. FACS-based FRET analysis in live cells, GST pull-down Biochemical and biophysical research communications Medium 20447381
2014 In nucleus pulposus (NP) cells, overexpressed FIH-1 suppresses HIF-1 activity, and co-transfection of full-length Mint3 or the Mint3 N-terminus abrogates this suppression under both normoxia and hypoxia. However, endogenous FIH-1 silencing does not significantly change classical HIF-1 target gene transcripts in NP cells, indicating the FIH-1–Mint3 axis does not control endogenous HIF-1 transcriptional activity in this cell type. HIF-1 reporter assay, co-transfection, nuclear import/export inhibitors, microarray after FIH-1 silencing The Journal of biological chemistry Medium 24867948
2016 Mint3 promotes K63-linked polyubiquitination of TRAF3, thereby enhancing IRF3 activation and IFN-β production downstream of TLR3/4 and RIG-I signaling in macrophages; Mint3 deficiency greatly attenuates antiviral immune responses and increases viral replication. Mint3 KO/knockdown in macrophages, ubiquitination assay (K63-linked), IRF3 activation assay, IFN-β reporter/ELISA, viral replication assay Proceedings of the National Academy of Sciences of the United States of America Medium 27698125
2016 In macrophages, Mint3 depletion attenuates NF-κB signaling (by increasing IκBα) and activates AMPK, reducing cytokine/chemokine production in response to influenza virus; Mint3-deficient mice show reduced inflammatory cytokines and neutrophil infiltration during influenza pneumonia without altering viral burden. Mint3 KO mice, siRNA knockdown, NF-κB pathway analysis (IκBα levels), AMPK activation assay, cytokine ELISA, neutrophil infiltration histology Scientific reports Medium 27883071
2017 Mint3/APBA3 in inflammatory monocytes maintains glycolysis-dependent chemotaxis and VEGFA expression, enabling CCR2+ monocyte recruitment to metastatic sites; host APBA3 induces VEGFA-mediated E-selectin expression in endothelial cells of target organs, promoting cancer cell extravasation and micrometastasis. E-selectin-neutralizing antibody abolished host APBA3-mediated metastatic formation. APBA3-deficient mice, bone marrow transplant, chemotaxis assay, VEGFA/E-selectin measurement, neutralizing antibody experiment, experimental metastasis model Proceedings of the National Academy of Sciences of the United States of America High 28507122
2021 The N-terminal region of Mint3 (approximately residues 78–88) is intrinsically disordered but undergoes a disorder-to-order transition upon binding FIH-1, with large enthalpy and entropy changes consistent with coupled folding-and-binding. Residues 78–88 constitute the core binding site for FIH-1, while flanking disordered regions contribute enthalpically without increasing affinity. Circular dichroism, NMR, hydrogen/deuterium exchange mass spectrometry, isothermal titration calorimetry with truncation mutants The Journal of biological chemistry High 34655613
2025 Mint3 interacts directly with STING, selectively enhances K63-linked polyubiquitination of STING, and facilitates STING translocation from the ER to the Golgi, which enhances STING–TBK1 interaction and downstream IRF3 activation and type I IFN production in response to HSV-1 infection and cytosolic DNA stimulation. Co-immunoprecipitation (MINT3–STING interaction), K63-polyubiquitination assay, STING translocation assay by microscopy, TBK1 interaction assay, Mint3 KO/knockdown in macrophages and in vivo viral challenge Cellular signalling Medium 40254147
2020 Mint3 promotes transcription of the oncogenic ubiquitin ligase SKP2 via HIF-1, and this Mint3–HIF-1–SKP2 axis accumulates cell cycle inhibitors p21 and p27 when depleted, supporting cancer cell proliferation, EMT, stemness, and chemoresistance in pancreatic cancer cells. shRNA knockdown, gene expression analysis, HIF-1 reporter, cell proliferation and chemoresistance assays, orthotopic xenograft mouse model Oncogene Medium 32826949
2023 Mint3 depletion reduces glycolytic adaptation of TNBC tumors to the microenvironment, causing energy stress that inactivates HSF1 via the AMPK/mTOR pathway, leading to decreased HSP70 expression and sensitization of TNBC tumors to chemotherapy in vivo. shRNA depletion, transcriptome analysis, AMPK/mTOR pathway assay, HSP70 inhibitor treatment, in vivo tumor model Cell death & disease Medium 38081808

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 X11L2, a new member of the X11 protein family, interacts with Alzheimer's beta-amyloid precursor protein. Biochemical and biophysical research communications 74 10049767
2009 Mint3 enhances the activity of hypoxia-inducible factor-1 (HIF-1) in macrophages by suppressing the activity of factor inhibiting HIF-1. The Journal of biological chemistry 55 19726677
2007 Mint3/X11gamma is an ADP-ribosylation factor-dependent adaptor that regulates the traffic of the Alzheimer's Precursor protein from the trans-Golgi network. Molecular biology of the cell 49 17959829
2004 Mint-3 regulates the retrieval of the internalized membrane-type matrix metalloproteinase, MT5-MMP, to the plasma membrane by binding to its carboxyl end motif EWV. The Journal of biological chemistry 46 14990567
2005 Rab6 interacts with the mint3 adaptor protein. Biological chemistry 35 16207088
2013 Recruitment of the Mint3 adaptor is necessary for export of the amyloid precursor protein (APP) from the Golgi complex. The Journal of biological chemistry 32 23965993
2011 Deletion of the Mint3/Apba3 gene in mice abrogates macrophage functions and increases resistance to lipopolysaccharide-induced septic shock. The Journal of biological chemistry 30 21778228
2008 Interaction of Mint3 with Furin regulates the localization of Furin in the trans-Golgi network. Journal of cell science 30 18544638
2017 Control of metastatic niche formation by targeting APBA3/Mint3 in inflammatory monocytes. Proceedings of the National Academy of Sciences of the United States of America 28 28507122
2017 DNA methylation of APBA3 and MCF2 in borderline personality disorder: Potential biomarkers for response to psychotherapy. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 27 29274998
2017 Mint3-mediated L1CAM expression in fibroblasts promotes cancer cell proliferation via integrin α5β1 and tumour growth. Oncogenesis 25 28504692
2016 Mint3 potentiates TLR3/4- and RIG-I-induced IFN-β expression and antiviral immune responses. Proceedings of the National Academy of Sciences of the United States of America 25 27698125
2020 Mint3 depletion restricts tumor malignancy of pancreatic cancer cells by decreasing SKP2 expression via HIF-1. Oncogene 22 32826949
2004 Bcr (breakpoint cluster region) protein binds to PDZ-domains of scaffold protein PDZK1 and vesicle coat protein Mint3. Journal of cell science 22 15494376
2014 FIH-1-Mint3 axis does not control HIF-1 transcriptional activity in nucleus pulposus cells. The Journal of biological chemistry 19 24867948
2016 Mint3/Apba3 depletion ameliorates severe murine influenza pneumonia and macrophage cytokine production in response to the influenza virus. Scientific reports 17 27883071
1999 Genomic organization of the human X11L2 gene (APBA3), a third member of the X11 protein family interacting with Alzheimer's beta-amyloid precursor protein. Neuroreport 15 10574372
2007 The X11L/X11beta/MINT2 and X11L2/X11gamma/MINT3 scaffold proteins shuttle between the nucleus and cytoplasm. Experimental cell research 14 18201694
2017 Mint3 in bone marrow-derived cells promotes lung metastasis in breast cancer model mice. Biochemical and biophysical research communications 10 28634075
2023 Mint3 as a Potential Target for Cooling Down HIF-1α-Mediated Inflammation and Cancer Aggressiveness. Biomedicines 9 36831085
2010 Characterizing the interaction between the Rab6 GTPase and Mint3 via flow cytometry based FRET analysis. Biochemical and biophysical research communications 9 20447381
2023 Mint3-depletion-induced energy stress sensitizes triple-negative breast cancer to chemotherapy via HSF1 inactivation. Cell death & disease 8 38081808
2021 Structural and thermodynamical insights into the binding and inhibition of FIH-1 by the N-terminal disordered region of Mint3. The Journal of biological chemistry 8 34655613
2020 Association of an APBA3 Missense Variant with Risk of Premature Ovarian Failure in the Korean Female Population. Journal of personalized medicine 6 33114509
2025 MINT3 promotes STING activation and facilitates antiviral immune responses. Cellular signalling 2 40254147
2020 Mint3 is dispensable for pancreatic and kidney functions in mice. Biochemistry and biophysics reports 1 33319072
2025 Mint3 as a Molecular Target Activated in the Early Stage of Hepatocarcinogenesis. International journal of molecular sciences 0 40003897

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