Affinage

BPIFB1

BPI fold-containing family B member 1 · UniProt Q8TDL5

Length
484 aa
Mass
52.4 kDa
Annotated
2026-06-09
26 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

BPIFB1 (LPLUNC1) is a secreted, glycosylated protein of upper-airway goblet cells and submucosal glands that serves dual roles as an innate-immune modulator of the mucosal surface and as a tumor suppressor in nasopharyngeal carcinoma (NPC) (PMID:20237794, PMID:29123267). In the airway it co-assembles with the gel-forming mucin MUC5B in secretory granules and in the secreted mucus mesh, acting as a trans-regulator of MUC5B levels and as a determinant of mucus biophysical/biochemical properties required for normal mucociliary clearance independently of ciliary beat frequency or epithelial ion transport (PMID:28851744, PMID:37847709). It dampens LPS-driven proinflammatory signalling in a TLR4-dependent manner, downregulating CD14/TLR4/MyD88 and TRAF6/NF-κB activity along with ERK, p38, and Akt phosphorylation (PMID:21900486, PMID:23746244). In NPC, BPIFB1 restrains proliferation and survival by suppressing MEK/ERK and JAK2/STAT3 signalling, lowering cyclin D1/CDK4 and AP-1 activity to block the G1–S transition (PMID:23708661, PMID:23650533, PMID:31933752). It inhibits migration, invasion, metastasis, and radioresistance through physical interaction with vitronectin (VTN) and vimentin (VIM), reducing VTN–integrin αV complexes and downstream FAK/Src/ERK signalling and EMT (PMID:29123267, PMID:29568064). Mechanistically, BPIFB1 stabilizes PHB1 by outcompeting the E3 ligase TRIM21 to block PHB1 ubiquitination, thereby restraining NF-κB and, via a PHB1–p53/c-Myc axis, shifting metabolism away from glycolysis toward oxidative phosphorylation (PMID:30886235, PMID:36382614). It further suppresses vasculogenic mimicry through a JNK/AP1–GLUT1–H3K27ac axis (PMID:34725462) and limits immune escape by repressing STAT1-driven PD-L1, an axis targeted by EBV miR-BART4 (PMID:38467887).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2010 Medium

    Established BPIFB1 as a secreted glycoprotein product of airway goblet cells, defining the cellular source and processed isoforms that anchor all later functional work.

    Evidence Antibody immunolocalization and western blotting of BAL fluid and primary airway epithelial secretions

    PMID:20237794

    Open questions at the time
    • Function of the secreted protein not addressed
    • Role of glycosylation isoforms undefined
  2. 2011 Medium

    Showed BPIFB1 attenuates LPS-induced innate immune responses specifically through TLR4 and not TLR2, establishing it as a pathway-selective anti-inflammatory mucosal factor.

    Evidence In vitro LPS stimulation with TLR pathway controls; duodenal Paneth-cell immunostaining

    PMID:21900486

    Open questions at the time
    • Direct LPS/TLR4 binding not demonstrated
    • Mechanism of TLR4 selectivity unresolved
  3. 2013 Medium

    Defined the intracellular signalling consequences of BPIFB1 anti-inflammatory action and its tumor-suppressive proliferation control, linking it to CD14/TLR4/MyD88/TRAF6/NF-κB, MEK/ERK, JNK, AP-1, and JAK2/STAT3 nodes.

    Evidence siRNA knockdown and kinase inhibitors in macrophages; overexpression with microarray, western blot, cell cycle, and in vivo tumor assays in NPC cells

    PMID:23650533 PMID:23708661 PMID:23746244

    Open questions at the time
    • Direct molecular target upstream of these pathways not identified
    • Connection between immune and tumor-suppressive functions unclear
  4. 2017 Medium

    Connected BPIFB1 to mucin biology and metastasis: it regulates MUC5B levels in vivo and physically engages VTN/VIM to suppress FAK/Src/ERK signalling and EMT-driven invasion.

    Evidence Bpifb1 knockout mice with allergen challenge and QTL mapping; reciprocal Co-IP/MS, IHC, and in vivo lung metastasis model

    PMID:28851744 PMID:29123267

    Open questions at the time
    • Domain mediating VTN/VIM interaction not mapped
    • Whether airway and tumor-suppressive functions use the same binding mode unknown
  5. 2018 Medium

    Extended the VTN axis to radioresistance, showing BPIFB1 reverses VTN-driven DNA-damage checkpoint activation and pro-survival signalling to radiosensitize NPC cells.

    Evidence Colony formation and survival assays with overexpression/knockdown and checkpoint protein western blots after irradiation

    PMID:29568064

    Open questions at the time
    • Direct effect on DNA repair machinery not distinguished from VTN-mediated indirect effect
  6. 2019 High

    Identified the central biochemical mechanism: BPIFB1 stabilizes PHB1 by competitively blocking TRIM21-mediated ubiquitination, providing a defined molecular route to NF-κB restraint and anti-tumour activity.

    Evidence Co-IP, in vitro ubiquitination assay, siRNA epistasis rescue, and NF-κB reporter assays

    PMID:30886235

    Open questions at the time
    • Structural basis of preferential BPIFB1-PHB1 affinity not solved
    • Whether secreted BPIFB1 or an intracellular pool mediates PHB1 binding unresolved
  7. 2021 Medium

    Linked BPIFB1 to metabolic and angiogenic reprogramming by showing it suppresses vasculogenic mimicry through a JNK/AP1-GLUT1-H3K27ac cascade.

    Evidence Overexpression, glycolysis and histone acetylation profiling, and tube-formation assays in NPC

    PMID:34725462

    Open questions at the time
    • Direct GLUT1 promoter regulation by AP1 not shown by ChIP in this context
  8. 2022 Medium

    Resolved the metabolic mechanism and placed BPIFB1 within circadian lung defense: it drives PHB1 nuclear translocation via 14-3-3σ to shift cells toward OXPHOS through a p53/c-Myc axis, and acts downstream of ATII-PER2 to protect against acute lung injury.

    Evidence Metabolic assays, nuclear fractionation, ATRA treatment; cell-type-specific Per2 knockout mice with P. aeruginosa ALI and pharmacological recapitulation

    PMID:35272486 PMID:36382614

    Open questions at the time
    • Mechanism of PER2-driven BPIFB1 transcription not defined
    • Whether metabolic and immune protective functions are coupled unknown
  9. 2023 High

    Established that BPIFB1 is required for mucociliary clearance through MUC5B co-assembly and mucus property control, while revealing a context-dependent pro-metastatic role in breast cancer via M2 macrophage polarization.

    Evidence Bpifb1 knockout mice with in vivo MCC and mucus characterization plus two-species colocalization; breast cancer/THP-1 co-culture and in vivo metastasis assays

    PMID:37702269 PMID:37847709

    Open questions at the time
    • Molecular basis of BPIFB1-MUC5B co-assembly not defined
    • Reconciliation of tumor-suppressive (NPC) versus pro-metastatic (breast) roles unresolved
  10. 2024 Medium

    Connected BPIFB1 to tumor immune evasion by showing it represses STAT1-driven PD-L1 and is silenced by EBV miR-BART4, defining a viral immune-escape axis.

    Evidence Overexpression/knockdown, ChIP, luciferase reporter, and CD8+ T cell apoptosis flow cytometry

    PMID:38467887

    Open questions at the time
    • Direct STAT1 binding mechanism by BPIFB1 not established
    • In vivo immune-escape consequences not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single secreted glycoprotein mechanistically reconciles its extracellular mucosal/immune roles with intracellular partner interactions (PHB1, VTN, VIM, STAT1) remains unresolved.
  • No structural model of BPIFB1 or its interaction interfaces
  • Subcellular trafficking that permits intracellular partner binding undefined
  • Determinants of opposing tumor-suppressive versus pro-metastatic outcomes unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005576 extracellular region 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
MUC5BPHB1TRIM21VIMVTN

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 BPIFB1 (LPLUNC1) inhibits IL-6-induced NPC cell proliferation by suppressing JAK2/STAT3 activation; overexpression decreased cyclin D1, Bcl-2, and JAK2/STAT3 phosphorylation while increasing Bax and p21, and also suppressed LPS-induced IL-6, IL-8, TNF-α, and IL-1β expression in vitro. Stable transfection overexpression in NPC cell lines, western blotting, in vivo tumor implantation model, THP-1 macrophage co-treatment assay Oncogene Medium 23708661
2013 BPIFB1 (LPLUNC1) inhibits NPC cell growth by downregulating MEK1, phospho-ERK1/2, phospho-JNK1/2, c-Myc, and c-Jun, reducing AP-1 transcriptional activity, and inhibiting cyclin D1, CDK4, and phospho-Rb, thereby delaying G1-to-S phase transition. Stable transfection overexpression, cDNA microarray, western blotting, in vitro proliferation and cell cycle assays, in vivo tumor formation PloS one Medium 23650533
2017 BPIFB1 inhibits NPC cell migration, invasion, and lung metastasis by interacting with vitronectin (VTN) and vimentin (VIM); it reduces VTN expression and VTN-integrin αV complex formation, thereby suppressing FAK/Src/ERK signalling and inhibiting VTN- or VIM-induced epithelial-mesenchymal transition. Co-immunoprecipitation coupled with mass spectrometry, western blotting, immunofluorescence, immunohistochemistry, in vitro migration/invasion assays, in vivo lung metastasis model British journal of cancer High 29123267
2018 BPIFB1 inhibits VTN-mediated radioresistance in NPC cells; VTN promotes G2/M arrest, DNA repair, ATM-Chk2 and ATR-Chk1 pathway activation, and anti-apoptotic effects after ionizing radiation, while BPIFB1 suppresses these VTN-dependent pro-survival responses to sensitize NPC cells to radiation. Colony formation assay, cell survival assay, overexpression and knockdown experiments, western blotting for DNA damage checkpoint proteins Cell death & disease Medium 29568064
2019 BPIFB1 (LPLUNC1) stabilizes PHB1 protein by competitively impairing PHB1 binding to E3 ubiquitin ligase TRIM21 (due to stronger BPIFB1-PHB1 affinity), thereby preventing TRIM21-mediated PHB1 ubiquitination and degradation; stabilized PHB1 then inhibits NF-κB activity, and PHB1 depletion reverses the anti-tumour effects of BPIFB1. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, western blotting, NF-κB reporter assay Oncogene High 30886235
2011 BPIFB1 (LPLUNC1) attenuates proinflammatory innate immune responses to V. cholerae and E. coli LPS in a TLR4-dependent, dose-dependent manner; it does not affect TLR2-mediated responses. The protein is expressed in Paneth cells in the duodenum. In vitro LPS stimulation assays, TLR4-dependent signalling readout, immunostaining of duodenal biopsies from cholera patients The Journal of infectious diseases Medium 21900486
2013 BPIFB1 reduces inflammatory responses to P. aeruginosa LPS in RAW264.7 macrophages by decreasing CD14, TLR4, and MyD88 expression, and inhibiting TRAF6/NF-κB activity and ERK1/2, p38, and Akt1 phosphorylation, as demonstrated by siRNA knockdown and specific kinase inhibitors. ELISA, western blotting, siRNA knockdown of MyD88/TRAF6/NF-κB, kinase inhibitor treatment, LPS stimulation assay Xi bao yu fen zi mian yi xue za zhi (Chinese journal of cellular and molecular immunology) Medium 23746244
2010 BPIFB1 (LPLUNC1) is a secreted, glycosylated protein produced by goblet cells of the airway epithelium and nasal passages, and by submucosal glands; it is present in bronchoalveolar lavage fluid as two glycosylated isoforms, and primary airway epithelial cells secrete identical isoforms during mucociliary differentiation. Affinity-purified antibody immunolocalization, western blotting of BAL and cell culture secretions, primary human airway epithelial cell cultures Histochemistry and cell biology Medium 20237794
2021 BPIFB1 inhibits vasculogenic mimicry in NPC by reducing GLUT1 transcription via downregulation of the JNK/AP1 signalling pathway; reduced glycolysis lowers histone H3K27 acetylation levels, which decreases expression of vasculogenic mimicry-related genes VEGFA, VE-cadherin, and MMP2. Overexpression studies, glycolysis assays, histone acetylation profiling, gene expression analysis, western blotting, vasculogenic mimicry tube-formation assay Oncogene Medium 34725462
2022 BPIFB1 (LPLUNC1) reduces glycolysis and increases oxidative phosphorylation in NPC cells via the PHB1-p53/c-Myc axis; BPIFB1 overexpression promotes phosphorylated PHB1 nuclear translocation through 14-3-3σ, increases p53, and decreases c-Myc expression. Overexpression and knockdown, western blotting, metabolic assays (glycolysis vs. OXPHOS), nuclear fractionation, all-trans retinoic acid (ATRA) treatment Cancer science Medium 36382614
2017 Bpifb1 knockout mice exhibit higher MUC5B airway mucin protein levels, and Bpifb1 mRNA and protein are upregulated in parallel with MUC5B after allergen challenge, identifying BPIFB1 as a novel trans-acting regulator of MUC5B. Genetic QTL mapping in Collaborative Cross mice, Bpifb1 knockout mouse model, allergen challenge, gene and protein expression analysis Genetics Medium 28851744
2023 BPIFB1 loss in mice reduces mucociliary clearance (MCC) in vivo independently of defects in epithelial ion transport or ciliary beat frequency; loss of BPIFB1 alters biophysical and biochemical properties of mucus. BPIFB1 co-localizes with MUC5B in secretory granules in mice and in the secreted mucus protein mesh in human airway epithelial cultures. Bpifb1 knockout mouse model, in vivo MCC measurement, mucus biophysical/biochemical characterization, colocalization by immunofluorescence in mouse tissue and human airway cultures American journal of physiology. Lung cellular and molecular physiology High 37847709
2022 BPIFB1 acts as a downstream target of alveolar type 2 cell-specific PER2 circadian signalling; intense light-elicited ATII-PER2 upregulates BPIFB1, which mediates lung-protective and anti-inflammatory effects during Pseudomonas aeruginosa-induced acute lung injury. Cell-type-specific Per2 knockout mice (ATII, endothelial, myeloid), P. aeruginosa ALI model, genome-wide mRNA array, nobiletin (PER2 enhancer) pharmacological recapitulation American journal of physiology. Lung cellular and molecular physiology Medium 35272486
2024 BPIFB1 suppresses PD-L1 expression in NPC cells by repressing STAT1, an upstream activator of PD-L1; BPIFB1 overexpression inhibits CD8+ T cell apoptosis. EBV-encoded miR-BART4 directly targets and inhibits BPIFB1, establishing an EBV-miR-BART4/BPIFB1/STAT1/PD-L1 immune-escape axis. Overexpression/knockdown, qRT-PCR, western blot, flow cytometry (CD8+ T cell apoptosis), chromatin immunoprecipitation (ChIP), luciferase reporter assay Biochemical genetics Medium 38467887
2023 BPIFB1 promotes metastasis of hormone receptor-positive breast cancer by stimulating M2-like polarization of macrophages; demonstrated using breast cancer cell/THP-1 macrophage co-culture, Transwell invasion assays, and animal experiments. BC/THP-1 macrophage co-culture system, qPCR, Transwell assay, animal experiments Cancer science Medium 37702269
2019 BPIFB1 overexpression induces apoptosis and DNA damage and arrests the cell cycle at G0/G1 in NPC cells via the MEK/ERK signalling pathway; MEK inhibitor U0126 reversed the proliferative effects of BPIFB1 silencing, confirming pathway dependency. Overexpression and siRNA knockdown, colony formation, cell cycle analysis, western blotting, MEK inhibitor (U0126) rescue experiment International journal of clinical and experimental pathology Medium 31933752
2017 BPIFB1 protein is localized in secretory granules of parotid gland acinar cells in NOD mice and is secreted into saliva, where it carries N-linked glycans reactive with Aleuria aurantia lectin, appearing as two spots of slightly different pI and molecular weight. Immunoblotting of subcellular fractions, immunohistochemistry, lectin blotting, saliva western blot Odontology Low 28748269

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 LPLUNC1 suppresses IL-6-induced nasopharyngeal carcinoma cell proliferation via inhibiting the Stat3 activation. Oncogene 105 23708661
2017 BPIFB1 (LPLUNC1) inhibits migration and invasion of nasopharyngeal carcinoma by interacting with VTN and VIM. British journal of cancer 79 29123267
2013 BPIFB1 is a lung-specific autoantigen associated with interstitial lung disease. Science translational medicine 78 24107778
2018 BPIFB1 (LPLUNC1) inhibits radioresistance in nasopharyngeal carcinoma by inhibiting VTN expression. Cell death & disease 67 29568064
2013 LPLUNC1 inhibits nasopharyngeal carcinoma cell growth via down-regulation of the MAP kinase and cyclin D1/E2F pathways. PloS one 49 23650533
2019 LPLUNC1 stabilises PHB1 by counteracting TRIM21-mediated ubiquitination to inhibit NF-κB activity in nasopharyngeal carcinoma. Oncogene 48 30886235
2011 LPLUNC1 modulates innate immune responses to Vibrio cholerae. The Journal of infectious diseases 43 21900486
2010 Human LPLUNC1 is a secreted product of goblet cells and minor glands of the respiratory and upper aerodigestive tracts. Histochemistry and cell biology 41 20237794
2020 Molecular biology of BPIFB1 and its advances in disease. Annals of translational medicine 35 32566588
2012 BPIFB1 (LPLUNC1) is upregulated in cystic fibrosis lung disease. Histochemistry and cell biology 30 22767025
2017 Association of innate defense proteins BPIFA1 and BPIFB1 with disease severity in COPD. International journal of chronic obstructive pulmonary disease 29 29296079
2015 Elevated sputum BPIFB1 levels in smokers with chronic obstructive pulmonary disease: a longitudinal study. American journal of physiology. Lung cellular and molecular physiology 29 25979078
2012 Differential localisation of BPIFA1 (SPLUNC1) and BPIFB1 (LPLUNC1) in the nasal and oral cavities of mice. Cell and tissue research 29 22986921
2015 Polymorphisms associated with expression of BPIFA1/BPIFB1 and lung disease severity in cystic fibrosis. American journal of respiratory cell and molecular biology 28 25574903
2021 BPIFB1 inhibits vasculogenic mimicry via downregulation of GLUT1-mediated H3K27 acetylation in nasopharyngeal carcinoma. Oncogene 21 34725462
2017 Identification of trans Protein QTL for Secreted Airway Mucins in Mice and a Causal Role for Bpifb1. Genetics 19 28851744
2023 BPIFB1 promotes metastasis of hormone receptor-positive breast cancer via inducing macrophage M2-like polarization. Cancer science 13 37702269
2022 Intense light-elicited alveolar type 2-specific circadian PER2 protects from bacterial lung injury via BPIFB1. American journal of physiology. Lung cellular and molecular physiology 11 35272486
2022 LPLUNC1 reduces glycolysis in nasopharyngeal carcinoma cells through the PHB1-p53/c-Myc axis. Cancer science 9 36382614
2019 Overexpression of BPIFB1 promotes apoptosis and inhibits proliferation via the MEK/ERK signal pathway in nasopharyngeal carcinoma. International journal of clinical and experimental pathology 8 31933752
2023 BPIFB1 loss alters airway mucus properties and diminishes mucociliary clearance. American journal of physiology. Lung cellular and molecular physiology 7 37847709
2015 Upregulation of Bpifb1 expression in the parotid glands of non-obese diabetic mice. Oral diseases 4 26769076
2024 BPIFB1, Serving as a Downstream Effector of EBV-miR-BART4, Blocks Immune Escape of Nasopharyngeal Carcinoma via Inhibiting PD-L1 Expression. Biochemical genetics 3 38467887
2024 CLCA1 and BPIFB1 are potential novel biomarkers for asthma: an iTRAQ analysis. Journal of thoracic disease 2 39552876
2017 Presence of BPIFB1 in saliva from non-obese diabetic mice. Odontology 1 28748269
2013 [Role of BPIFB1 in regulating inflammatory response of RAW264.7 cells infected by P.aeruginosa]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 1 23746244

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