{"gene":"DMBT1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":1997,"finding":"DMBT1 was identified as a novel gene on chromosome 10q25.3-26.1 encoding a member of the scavenger receptor cysteine-rich (SRCR) superfamily, with homozygous intragenic deletions detected in medulloblastoma and glioblastoma multiforme cell lines and primary tumors, and lack of expression demonstrated in brain-tumor cell lines.","method":"Representational difference analysis, molecular cloning, PCR-based deletion analysis, expression analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — foundational cloning paper with multiple orthogonal methods (RDA, cloning, deletion mapping, expression analysis); independently replicated across subsequent studies","pmids":["9288095"],"is_preprint":false},{"year":1997,"finding":"gp-340 (DMBT1) was purified from human bronchioalveolar lung washings and shown to bind surfactant protein D (SP-D) in a calcium-dependent, maltose-independent manner (protein-protein interaction via the CRD of SP-D), and was localized to the surface of and within alveolar macrophages.","method":"Protein purification, calcium-dependent binding assay, inhibition with maltose, immunohistochemistry, N-glycosidase F digestion, SDS-PAGE","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct biochemical binding assay with inhibition controls, replicated by multiple subsequent studies confirming SP-D interaction","pmids":["9153228"],"is_preprint":false},{"year":1999,"finding":"The primary structure of gp-340 (DMBT1) was established by molecular cloning, revealing a polypeptide of 2,413 amino acids with 13 SRCR domains, SRCR-interspersed domains, two CUB domains, a 14th SRCR domain, and a zona pellucida domain. gp-340 was confirmed to bind SP-D calcium-dependently. The protein is found in a soluble form and membrane-associated on alveolar macrophages, with SP-D and gp-340 co-localizing in the same phagosome/phagolysosome compartments.","method":"Molecular cloning (7,686-bp cDNA), RT-PCR, immunohistochemistry, co-localization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — complete cDNA cloning with domain mapping, replicated SP-D binding, functional localization in macrophage phagosomes","pmids":["10485905"],"is_preprint":false},{"year":1999,"finding":"Hensin, the polarity-reversal extracellular matrix protein that converts beta-intercalated cells to alpha-intercalated cell phenotype, is an alternatively spliced product of the DMBT1 gene. Mouse genomic hensin maps to chromosome 7F4, syntenic to human 10q25-26.","method":"cDNA cloning, genomic Southern hybridization, chromosomal synteny mapping, immunoblotting with domain-specific antibodies","journal":"The American journal of physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — molecular cloning plus genomic mapping, independently confirmed by subsequent knockout study","pmids":["10444583"],"is_preprint":false},{"year":2000,"finding":"DMBT1 protein isoforms are identical to the collectin-binding protein gp-340 involved in respiratory immune defense; DMBT1 is expressed throughout the immune system; its orthologs CRP-ductin (mouse) and hensin (rabbit) are implicated in epithelial differentiation, indicating DMBT1 has dual functions in immune defense and epithelial development.","method":"Western blot, immunohistochemistry, RT-PCR expression analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — immunoblot identity confirmation and tissue expression, single lab, multiple methods","pmids":["10749143"],"is_preprint":false},{"year":2000,"finding":"Salivary agglutinin is identical to lung gp-340 (DMBT1) as confirmed by MALDI-TOF mass spectrometry peptide sequencing and immunoblotting. Salivary agglutinin/gp-340 binds Streptococcus mutans, Helicobacter pylori, Streptococcus agalactiae, and oral commensal streptococci. The salivary form carries sialyl Le(x) carbohydrate not present on lung gp-340, indicating tissue-specific glycoforms.","method":"Protein purification, MALDI-TOF MS, HPLC peptide sequencing, immunoblotting with cross-reactive antibodies, bacterial binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mass spectrometry sequence identity plus immunoblot cross-reactivity, replicated by subsequent studies","pmids":["11007786"],"is_preprint":false},{"year":2001,"finding":"Salivary agglutinin is identical to gp-340/DMBT1, confirmed by Q-TOF tandem MS peptide sequencing showing 100% identity to SRCR domain sequences of gp-340. Agglutinin and gp-340 bind S. mutans and surfactant protein D in a similar manner, and share histochemical distribution in submandibular salivary glands.","method":"Q-TOF tandem MS, Western blotting with cross-reactive monoclonal antibodies, bacterial binding assay, SP-D binding assay, immunohistochemistry","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct protein sequencing confirming identity, replicated with multiple orthogonal methods","pmids":["11563989"],"is_preprint":false},{"year":2002,"finding":"The bacteria-binding domain of salivary agglutinin/DMBT1 was localized to the SRCR domains. A 16-amino-acid consensus peptide (SRCRP2: QGRVEVLYRGSWGTVC) derived from the SRCR domain was identified as the minimal bacteria-binding site, capable of binding and agglutinating S. mutans and other bacteria.","method":"Endoproteinase Lys-C digestion, synthetic consensus peptides, bacterial adhesion and agglutination assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — peptide mapping with synthetic peptides and functional binding assays; confirmed by subsequent mutagenesis studies","pmids":["12050164"],"is_preprint":false},{"year":2003,"finding":"Mouse CRP-ductin (the DMBT1 ortholog) binds human SP-D in a calcium-dependent, maltose-insensitive manner and shows calcium-dependent binding to both gram-positive and gram-negative bacteria, supporting a conserved role in mucosal immune defense.","method":"Protein purification, calcium-dependent binding assay, bacterial binding assay, immunoblotting, RT-PCR","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical binding assays with inhibition controls in mouse ortholog, single lab","pmids":["12884308"],"is_preprint":false},{"year":2004,"finding":"The minimal bacteria-binding motif on DMBT1 was narrowed to an 11-amino-acid sequence (DMBT1pbs1: GRVEVLYRGSW) within the SRCR domains. Alanine substitution scanning revealed that VEVL and the terminal Trp are critical residues. Only DMBT1 orthologs, not other SRCR proteins, bound bacteria via this motif.","method":"Overlapping synthetic peptides, alanine substitution scanning, bacterial binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis (alanine scan) identifying critical residues, multiple bacteria tested","pmids":["15355985"],"is_preprint":false},{"year":2004,"finding":"gp340 (DMBT1) binds to the V3 loop region of HIV-1 gp120 (a linear, conserved sequence near the V3 stem critical for chemokine receptor interaction). This binding is distinct from the CD4-binding site, is enhanced by prebinding of sCD4 to gp120, and mediates inhibition of HIV-1 infection.","method":"V3 peptide binding assays, HIV-1 infection inhibition assays, sCD4 competition assay","journal":"AIDS research and human retroviruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct peptide binding and functional infection assay, single lab","pmids":["15242536"],"is_preprint":false},{"year":2005,"finding":"Fluid-phase gp340 and surface-adsorbed gp340 display differential bacterial recognition: fluid-phase gp340 aggregates bacteria via antigen I/II (SspA/SspB) polypeptides of S. gordonii, while surface-bound gp340 mediates adhesion via the sialic acid-binding adhesin Hsa. Mga virulence regulator deletion in S. pyogenes increases aggregation by gp340.","method":"Bacterial aggregation and adhesion assays with purified proteins, isogenic mutants lacking specific adhesins, hydroxylapatite surface-adsorption","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mutant approach with defined adhesin deletions, multiple bacterial species, single lab","pmids":["15784568"],"is_preprint":false},{"year":2005,"finding":"DMBT1 expression in gastric epithelial cells (AGS) is regulated by ERK and PKC signaling: high ERK activity suppresses DMBT1, while ERK inhibition or high cell density (causing G0/G1 arrest) induces DMBT1. DMBT1 knockdown by siRNA reduced PMA-induced trefoil factor 1 (TFF1) induction, suggesting DMBT1 acts at an early stage of gastric epithelial differentiation.","method":"RT-PCR, siRNA knockdown, ERK inhibitor (PD98059), CFSE labeling for cell growth, flow cytometry (G0/G1 arrest analysis)","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus siRNA knockdown with defined readouts, single lab","pmids":["15760920"],"is_preprint":false},{"year":2006,"finding":"The N-terminal SRCR domain of gp-340 (a 35-kDa truncated recombinant protein comprising the first SRCR and half of the first SID) is sufficient to bind HIV-1 gp120 V3 sequences in a Ca2+-dependent manner and inhibits both CCR5- and CXCR4-tropic HIV-1 isolates, similar to the full-length protein.","method":"Recombinant protein expression in 293 cells, Ca2+-dependent binding assay, HIV-1 infection inhibition assay","journal":"AIDS research and human retroviruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-deletion approach with functional assay, single lab","pmids":["16796526"],"is_preprint":false},{"year":2007,"finding":"gp340 expressed on human genital epithelial cells binds HIV-1 envelope via a specific protein-protein interaction, allowing otherwise subinfectious amounts of HIV to efficiently infect target cells and extending the duration of viral infectivity.","method":"Cell surface expression analysis, HIV binding assays, HIV infection assays with blocking antibodies/peptides","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — blocking antibodies/peptides confirming specific interaction mechanism, single lab","pmids":["17709527"],"is_preprint":false},{"year":2007,"finding":"DMBT1 is a target gene of the intracellular pathogen receptor NOD2 via NF-κB activation in intestinal epithelial cells. TNF-α and LPS up-regulate DMBT1 expression. DMBT1 inhibits Salmonella enterica cytoinvasion and suppresses LPS- and muramyl dipeptide-induced NF-κB activation and cytokine secretion in vitro.","method":"In vitro stimulation, NF-κB reporter assay, siRNA knockdown, bacterial invasion assay, cytokine ELISA","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate–Strong — multiple orthogonal methods (NF-κB reporter, bacterial invasion assay, cytokine measurement, NOD2 mutant patient tissue), single lab but comprehensive","pmids":["17548659"],"is_preprint":false},{"year":2007,"finding":"Dmbt1-deficient mice display enhanced susceptibility to dextran sulfate sodium-induced colitis with elevated Tnf, Il6, and Nod2 expression, demonstrating that DMBT1 confers mucosal protection in vivo. A deletion allele of DMBT1 with reduced SRCR domain-coding exons is associated with increased Crohn's disease risk.","method":"Dmbt1-/- knockout mice, DSS-induced colitis model, qRT-PCR, immunohistochemistry, genetic association study","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse model with defined phenotype plus human genetic association, replicated finding","pmids":["17983803"],"is_preprint":false},{"year":2007,"finding":"gp340 aggregates Group A streptococci by binding GAS pili. Pilus-defective GAS mutants fail to aggregate in saliva and show reduced gp340 binding. Heterologous expression of GAS pili on Lactococcus lactis confers gp340-mediated aggregation. gp340-mediated aggregation reduces bacterial adhesion to human epithelial cells.","method":"Pilus-defective GAS mutants, heterologous pilus expression, purified gp340 aggregation assay, bacterial adhesion assay","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — isogenic mutants and heterologous expression reconstituting phenotype, functional adhesion readout","pmids":["18452511"],"is_preprint":false},{"year":2008,"finding":"A common bacteria-binding motif RVEVLYxxxSW within DMBT1 SRCR domains mediates binding of a broad range of bacteria. Alanine substitution scanning of SRCRP2 showed that 8 residues are involved in binding with species-specific variation, but the core VxVxY and W residues are always required.","method":"Alanine substitution peptide scan, bacterial adhesion and agglutination assays with multiple species","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — systematic mutagenesis with functional assays across multiple bacterial species, single lab","pmids":["18713006"],"is_preprint":false},{"year":2008,"finding":"Monocyte-derived macrophages express gp340, and HIV-1 infection of macrophages is decreased when the viral envelope cannot bind gp340. Inhibition occurred at the level of membrane fusion for M-, T-, and dual-tropic envelopes, suggesting gp340 enhances HIV-1 infection of macrophages by concentrating virus locally.","method":"Macrophage expression analysis, HIV infection inhibition with anti-gp340 antibodies/peptides blocking envelope binding, fusion assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — blocking antibody approach with specific fusion-level readout, single lab","pmids":["18641344"],"is_preprint":false},{"year":2008,"finding":"Muclin (Dmbt1 product) deficiency in mice impairs exocrine pancreatic function: attenuated neurohormonal-stimulated amylase release from acinar cells and retarded trafficking of newly synthesized secretory proteins to the stimulus-releasable pool, as shown by pulse-chase analysis.","method":"Dmbt1-/- knockout mice, amylase release assay, [35S]Met/Cys pulse-chase protein trafficking analysis","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse model with defined biochemical phenotype (pulse-chase), single lab","pmids":["18202109"],"is_preprint":false},{"year":2009,"finding":"gp340 mediates transcytosis of HIV-1 across genital tract-derived cell lines and primary endocervical tissue from apical to basolateral surfaces. This transcytosis is blocked by antibodies or peptides that disrupt gp340-HIV envelope interaction. Heparan sulfate moieties on gp340 also participate in mediating transcytosis.","method":"Transwell transcytosis assay with primary endocervical tissue, blocking antibodies/peptides, heparan sulfate perturbation","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary tissue model with specific blocking reagents, single lab","pmids":["19553331"],"is_preprint":false},{"year":2009,"finding":"Leucine-rich repeat (Lrr) motifs on bacterial surface proteins (S. pyogenes Spy0843, S. agalactiae LrrG, T. forsythia BspA) serve as recognition motifs for human gp340/DMBT1. The Lrr region mediates binding to gp340, and VEVLXXXXW-containing peptides inhibit this binding, implicating a gp340 core peptide distinct from the XXXXW motif.","method":"Mass spectrometry sequencing, gene inactivation (bacterial mutants), recombinant truncated protein binding assay, peptide inhibition assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and recombinant protein approach with multiple bacterial species, single lab","pmids":["19465482"],"is_preprint":false},{"year":2010,"finding":"Deletion of hensin/DMBT1 from intercalated cells blocks conversion of beta- to alpha-intercalated cells in the renal collecting tubule, causing complete distal renal tubular acidosis (dRTA). Polymerization and ECM deposition of hensin requires beta1 integrin activation; conditional deletion of beta1 integrin from intercalated cells produces an identical phenotype.","method":"Conditional Dmbt1 knockout and beta1-integrin knockout mice, immunofluorescence localization of V-ATPase/pendrin/kAE1, acid-feeding challenge, electron microscopy","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent conditional knockout models with identical phenotype, mechanistic epistasis (hensin requires beta1 integrin), multiple orthogonal readouts","pmids":["21098262"],"is_preprint":false},{"year":2010,"finding":"DMBT1 expression in intestinal epithelial cells is induced by IL-22 through STAT3 tyrosine phosphorylation and NF-κB activation. The IL-22-responsive element was mapped to positions -187 to -179 in the DMBT1 promoter by deletion analysis and EMSA.","method":"Microarray, siRNA knockdown of STAT3, MEK/PI3K/NF-κB inhibitors, promoter deletion luciferase assay, EMSA","journal":"Inflammatory bowel diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mapping by deletion and EMSA, pathway inhibitors with siRNA, single lab","pmids":["20824812"],"is_preprint":false},{"year":2011,"finding":"Salivary agglutinin (DMBT1) activates complement via the lectin pathway (MBL pathway): antibodies against mannose-binding lectin (MBL) block C4 deposition on SAG-coated plates, SAG induces no C4 deposition in MBL-deficient sera, and periodate treatment of SAG (removing carbohydrate) abolishes MBL pathway activation.","method":"C4 deposition ELISA on SAG-coated microplates, MBL-blocking antibodies, MBL-deficient sera, periodate carbohydrate oxidation","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic complement pathway assignment using pathway-specific deficient sera and glycan perturbation, single lab","pmids":["21920605"],"is_preprint":false},{"year":2013,"finding":"Staphylococcus aureus surface protein SasA is responsible for binding to gp340/DMBT1. Inactivation of the sasA gene reduces S. aureus binding to gp340-coated surfaces. Recombinant SasA binds gp340, inhibited by N-acetylneuraminic acid; surface plasmon resonance shows rSasA binds NeuAcα(2-3)Galβ(1-4)GlcNAc structures on gp340.","method":"Gene inactivation (sasA mutant), recombinant protein binding assay, sialic acid inhibition, surface plasmon resonance","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — genetic mutant plus recombinant protein SPR with defined carbohydrate inhibition, single lab with multiple orthogonal methods","pmids":["23439307"],"is_preprint":false},{"year":2013,"finding":"DMBT1(gp340) binds to solid-phase dimeric TFF3 in a calcium-dependent manner but does not bind monomeric TFF3, TFF2, or glycosylated TFF2, establishing a specific interaction requiring TFF3 dimerization.","method":"ELISA-based binding assay with recombinant TFF isoforms, calcium dependency analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding ELISA with defined isoform specificity controls and calcium dependency, single lab","pmids":["23691218"],"is_preprint":false},{"year":2013,"finding":"The non-coding DMBT1 SNP rs2981804 modifies DNA binding sites for transcription factors CREB1 and ATF-2, and the genomic region comprising rs2981804 acts as a transcriptional regulator in vitro; the CD risk allele is associated with decreased intestinal DMBT1 expression. IL-22 induces DMBT1 expression in intestinal epithelial cells via STAT3, ATF-2, and CREB1.","method":"Electrophoretic mobility shift assay (EMSA), luciferase reporter assay, siRNA knockdown, quantitative PCR, Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and luciferase assay with siRNA confirmation, single lab, multiple methods","pmids":["24223725"],"is_preprint":false},{"year":2017,"finding":"DMBT1 purified from human saliva inhibits twitching motility of Pseudomonas aeruginosa and prevents bacterial traversal of human corneal epithelial cells in vitro and reduces disease in a murine corneal infection model. DMBT1 does not affect PilA expression or intracellular cAMP levels, but dot-immunoblot assays show purified DMBT1 directly binds P. aeruginosa pili, suggesting inhibition involves a direct pili interaction.","method":"Protein fractionation and mass spectrometry identification, immunoprecipitation, purified DMBT1 twitching assay, dot-immunoblot pili binding assay, epithelial cell traversal assay, murine corneal infection model","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification, direct pili binding assay, in vivo model, single lab with multiple orthogonal methods","pmids":["28489917"],"is_preprint":false},{"year":2018,"finding":"DMBT1 protein is enriched in exosomes from human urine-derived stem cells (USC-Exos) and is required for USC-Exos-induced promotion of angiogenic responses of endothelial cells in vitro and for angiogenesis and wound healing in diabetic mice in vivo.","method":"Exosome proteomics, DMBT1 knockdown in USC-Exos, in vitro angiogenesis assays, streptozotocin-induced diabetic mouse wound healing model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function knockdown in exosome context with in vitro and in vivo readouts, single lab","pmids":["29556344"],"is_preprint":false},{"year":2020,"finding":"Crystal/structural analysis of DMBT1 (SALSA) SRCR domains 1 and 8 revealed a novel universal ligand-binding mechanism: the binding interface incorporates a dual cation-binding site that is highly conserved across the SRCR superfamily, suggesting this mechanism is applicable to all SRCR domains.","method":"Structural determination (crystallography implied), cation-binding site identification, comparative analysis across SRCR superfamily","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural determination with functional validation of binding mechanism, single lab","pmids":["32098784"],"is_preprint":false},{"year":2020,"finding":"DMBT1 overexpression in ovarian cancer cells inhibits proliferation, migration, and invasion, and immunoprecipitation reveals a direct interaction between DMBT1 and galectin-3. DMBT1 decreases galectin-3 expression and inhibits PI3K/AKT phosphorylation; overexpression of galectin-3 reverses DMBT1-mediated tumor suppression.","method":"Overexpression, CCK-8 proliferation assay, wound healing/transwell invasion assay, immunoprecipitation, Western blot for PI3K/AKT phosphorylation","journal":"Cell biochemistry and function","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with pharmacological pathway inference, single lab, no rescue or reconstitution","pmids":["32424818"],"is_preprint":false},{"year":2022,"finding":"Exosomes derived from MSCs pretreated with ischemic heart extracts contain elevated DMBT1; silencing DMBT1 in MSCs reduces DMBT1 in exosomes and impairs HUVEC proliferation and migration, along with decreased p-Akt, beta-catenin, and VEGF, suggesting DMBT1 delivery via exosomes promotes angiogenesis through Akt/beta-catenin/VEGF signaling.","method":"Proteomics, DMBT1 siRNA knockdown, MTT and wound healing assays, Western blot for pathway components","journal":"Cell transplantation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, siRNA knockdown with pathway Western blot but no reconstitution or direct binding confirmation","pmids":["35726847"],"is_preprint":false}],"current_model":"DMBT1 (also known as gp-340, SALSA, salivary agglutinin, and hensin) is a large, multi-domain scavenger receptor cysteine-rich (SRCR) secreted glycoprotein that functions as a broad-spectrum pattern recognition molecule at mucosal surfaces: its conserved SRCR domain VEVLXXXXW motif directly binds bacterial pili, surface proteins (including LRR-containing proteins), and other pathogen-associated structures to agglutinate and clear bacteria; via its SRCR domains it also binds HIV-1 gp120 at the V3 loop in a calcium-dependent manner to inhibit or facilitate infection depending on cell context; it interacts with surfactant proteins A and D, IgA, lactoferrin, complement initiators (C1q, MBL, ficolins), and dimeric TFF3 through its SRCR domains and associated glycans; its structural basis involves a dual cation-binding site in SRCR domains that mediates ligand binding conserved across the SRCR superfamily; as hensin/DMBT1, its ECM polymerization (requiring beta1-integrin activation) drives terminal differentiation of renal intercalated cells from HCO3-secreting (beta) to acid-secreting (alpha) phenotype; its expression is regulated by NOD2/NF-κB, IL-22/STAT3/NF-κB, and ERK signaling; and it promotes angiogenesis when delivered via exosomes."},"narrative":{"mechanistic_narrative":"DMBT1 is a large, multi-domain scavenger receptor cysteine-rich (SRCR) glycoprotein that functions as a broad-spectrum pattern-recognition molecule at mucosal surfaces and, in an alternatively spliced/orthologous form (hensin/CRP-ductin/muclin), as an extracellular matrix regulator of epithelial differentiation [PMID:9288095, PMID:10485905, PMID:10444583, PMID:10749143]. The protein — independently characterized as lung gp-340 and salivary agglutinin and shown by mass spectrometry to be identical — comprises 13–14 SRCR domains interspersed with SID and CUB domains and a terminal zona pellucida domain [PMID:10485905, PMID:11007786, PMID:11563989]. Its bacteria-binding activity maps to a conserved SRCR motif: peptide and alanine-scanning studies narrowed the minimal site to an 11-residue sequence (GRVEVLYRGSW) within which the core VEVL and terminal tryptophan are critical, defining a common RVEVLYxxxSW recognition motif that binds a broad range of bacteria including S. mutans, group A streptococci, and S. aureus [PMID:12050164, PMID:15355985, PMID:18713006]. Through these SRCR domains DMBT1 recognizes bacterial pili, antigen I/II polypeptides, leucine-rich-repeat surface proteins (Spy0843, LrrG, BspA), and the sialoadhesin SasA, agglutinating bacteria and reducing their epithelial adhesion [PMID:15784568, PMID:18452511, PMID:19465482, PMID:23439307, PMID:28489917]. A dual cation-binding site within the SRCR fold provides the structural basis for this conserved ligand recognition [PMID:32098784]. DMBT1 also binds surfactant protein D calcium-dependently and co-localizes with it in macrophage phagosomes, and it activates complement via the MBL/lectin pathway through its carbohydrate moieties [PMID:9153228, PMID:10485905, PMID:21920605]. In innate immune signaling it is a NOD2/NF-κB and IL-22/STAT3 target gene that dampens LPS- and muramyl-dipeptide-induced NF-κB activation and confers mucosal protection: Dmbt1-deficient mice show enhanced DSS colitis and a reduced-SRCR deletion allele is associated with Crohn's disease risk [PMID:17548659, PMID:17983803, PMID:20824812]. As hensin, DMBT1 polymerization and ECM deposition — requiring beta1-integrin activation — drives terminal differentiation of renal intercalated cells, and its loss causes complete distal renal tubular acidosis [PMID:21098262]. It binds HIV-1 gp120 at the V3 loop in a calcium-dependent manner through its N-terminal SRCR domain, an interaction that inhibits infection in some contexts yet promotes viral capture, transcytosis, and infection of mucosal target cells in others [PMID:15242536, PMID:16796526, PMID:17709527, PMID:19553331].","teleology":[{"year":1997,"claim":"Established DMBT1 as a candidate tumor-suppressor gene of the SRCR superfamily, defining its genomic locus and linking its loss to brain malignancy.","evidence":"Representational difference analysis, cloning, and deletion mapping in medulloblastoma/glioblastoma lines and tumors","pmids":["9288095"],"confidence":"High","gaps":["No protein-level function defined at this stage","Causality of deletions in tumorigenesis not tested by rescue"]},{"year":1997,"claim":"Identified the secreted/macrophage-associated protein gp-340 and its calcium-dependent SP-D interaction, situating DMBT1 in respiratory innate defense before the gp-340/DMBT1 identity was formalized.","evidence":"Protein purification from lung washings, calcium-dependent maltose-insensitive SP-D binding, immunohistochemistry","pmids":["9153228"],"confidence":"High","gaps":["Full primary structure and domain architecture not yet known","Physiological consequence of SP-D binding not established"]},{"year":1999,"claim":"Resolved the complete domain architecture (13+1 SRCR, SID, CUB, ZP domains) and unified gp-340 with the renal differentiation factor hensin as DMBT1 splice products, revealing dual immune and epithelial roles.","evidence":"cDNA cloning, domain mapping, genomic synteny mapping, immunoblotting","pmids":["10485905","10444583"],"confidence":"High","gaps":["Which domains mediate which functions not yet mapped","Splice-isoform tissue distribution incompletely defined"]},{"year":2000,"claim":"Mass-spectrometric identity established that salivary agglutinin, lung gp-340, and DMBT1 are the same molecule with tissue-specific glycoforms, explaining its broad bacterial-binding reputation across mucosa.","evidence":"MALDI-TOF/Q-TOF peptide sequencing, immunoblot cross-reactivity, bacterial binding assays","pmids":["11007786","11563989","10749143"],"confidence":"High","gaps":["Functional role of tissue-specific glycans not dissected","Binding domain not yet localized"]},{"year":2002,"claim":"Localized bacterial recognition to the SRCR domains and defined a minimal binding peptide, converting a multi-domain protein into a tractable molecular recognition unit.","evidence":"Proteolytic mapping plus synthetic SRCRP2 consensus peptide binding/agglutination assays","pmids":["12050164"],"confidence":"High","gaps":["Individual critical residues not yet identified","Structural basis of peptide-ligand contact unknown"]},{"year":2004,"claim":"Mutagenesis pinpointed VEVL and the terminal Trp as essential and showed only DMBT1 orthologs use this motif, defining the chemistry of broad bacterial recognition.","evidence":"Overlapping peptides and alanine-substitution scanning with bacterial binding assays","pmids":["15355985"],"confidence":"High","gaps":["Bacterial counter-ligands for many species still unknown","Whether motif binds protein or glycan ligands not resolved"]},{"year":2004,"claim":"Demonstrated DMBT1 binds the conserved HIV-1 gp120 V3 loop independently of the CD4 site and inhibits infection, extending its pattern recognition to a virus.","evidence":"V3 peptide binding, sCD4 competition, HIV infection inhibition assays","pmids":["15242536"],"confidence":"Medium","gaps":["Context-dependence of inhibition versus enhancement unresolved","Domain responsible not yet mapped"]},{"year":2005,"claim":"Showed fluid-phase versus surface-adsorbed DMBT1 recognize bacteria via distinct adhesins, establishing that immobilization state dictates recognition outcome (aggregation versus adhesion).","evidence":"Aggregation/adhesion assays with isogenic adhesin mutants and surface adsorption","pmids":["15784568"],"confidence":"Medium","gaps":["Structural change upon surface adsorption not defined","Single bacterial genus tested for the mechanism"]},{"year":2007,"claim":"Positioned DMBT1 within innate immune signaling as a NOD2/NF-κB target that feedback-suppresses NF-κB and limits bacterial invasion, and demonstrated in vivo mucosal protection with a human Crohn's disease association.","evidence":"NF-κB reporters, siRNA, Salmonella invasion assays; Dmbt1-/- DSS colitis model and genetic association","pmids":["17548659","17983803"],"confidence":"High","gaps":["Mechanism by which DMBT1 dampens NF-κB signaling not defined","Causal SRCR-deletion variant biology in patients incomplete"]},{"year":2008,"claim":"Refined the universal bacterial-binding motif (RVEVLYxxxSW) with species-specific residue usage and linked DMBT1 deficiency to impaired pancreatic exocrine secretory trafficking, broadening its functional scope.","evidence":"Alanine scan across multiple species; Dmbt1-/- pancreatic amylase release and pulse-chase trafficking","pmids":["18713006","18202109","18452511"],"confidence":"Medium","gaps":["How a secreted SRCR protein influences intracellular secretory trafficking unclear","Direct pili counter-receptor structure not solved"]},{"year":2009,"claim":"Resolved the dual HIV outcome by showing genital/macrophage DMBT1 concentrates virus, enhances fusion, and mediates apical-to-basolateral transcytosis, reframing it as a context-dependent infection facilitator.","evidence":"Macrophage/genital epithelial infection and fusion assays, transwell transcytosis with primary endocervical tissue, blocking reagents, heparan sulfate perturbation","pmids":["18641344","17709527","19553331"],"confidence":"Medium","gaps":["What determines inhibition versus enhancement in vivo unknown","Relative contribution of SRCR versus heparan sulfate moieties unresolved"]},{"year":2009,"claim":"Identified bacterial leucine-rich-repeat surface proteins as a recurring class of DMBT1 ligands, implicating a core peptide distinct from the XXXXW motif.","evidence":"Mass spectrometry, bacterial gene inactivation, recombinant truncated protein and peptide inhibition assays","pmids":["19465482"],"confidence":"Medium","gaps":["Structural mapping of the LRR-binding core peptide not done","Single lab"]},{"year":2010,"claim":"Defined the hensin/DMBT1 differentiation mechanism: beta1-integrin-dependent ECM polymerization converts beta- to alpha-intercalated cells, and its loss causes complete distal renal tubular acidosis.","evidence":"Conditional Dmbt1 and beta1-integrin knockout mice, V-ATPase/pendrin/kAE1 immunofluorescence, acid-feeding challenge","pmids":["21098262"],"confidence":"High","gaps":["Molecular link between ECM polymerization and intracellular polarity reversal not defined","Receptor downstream of beta1 integrin not identified"]},{"year":2010,"claim":"Mapped IL-22/STAT3-NF-κB and CREB1/ATF-2 transcriptional control of DMBT1 and tied a non-coding risk SNP to reduced intestinal expression, connecting cytokine signaling to mucosal defense capacity.","evidence":"Microarray, STAT3 siRNA, pathway inhibitors, promoter deletion luciferase, EMSA","pmids":["20824812","24223725"],"confidence":"Medium","gaps":["Quantitative effect of expression on host protection not measured","In vivo relevance of the SNP regulation not tested"]},{"year":2011,"claim":"Showed DMBT1 activates the lectin (MBL) complement pathway through its carbohydrate, linking pattern recognition to complement-mediated clearance.","evidence":"C4 deposition ELISA with MBL-blocking antibodies, MBL-deficient sera, periodate glycan oxidation","pmids":["21920605"],"confidence":"Medium","gaps":["Identity of the MBL-engaging glycan not defined","Downstream opsonization/clearance not measured"]},{"year":2013,"claim":"Expanded the ligand repertoire with the S. aureus sialoadhesin SasA and dimeric TFF3, both engaged via defined carbohydrate or dimerization-dependent contacts.","evidence":"sasA inactivation, SPR with defined sialyl glycans; ELISA binding with TFF isoform controls","pmids":["23439307","23691218"],"confidence":"Medium","gaps":["Functional consequence of TFF3 binding not established","In vivo relevance of SasA interaction untested"]},{"year":2017,"claim":"Demonstrated DMBT1 directly binds Pseudomonas aeruginosa pili to inhibit twitching motility and corneal traversal in vivo, showing motility/virulence suppression beyond simple agglutination.","evidence":"Mass spectrometry identification, dot-immunoblot pili binding, twitching and epithelial traversal assays, murine corneal infection model","pmids":["28489917"],"confidence":"Medium","gaps":["Mechanism by which pili binding inhibits motility unresolved","PilA/cAMP shown unaffected, leaving signaling step unknown"]},{"year":2020,"claim":"Provided the structural basis for DMBT1 ligand recognition: a dual cation-binding site in SRCR domains 1 and 8 conserved across the SRCR superfamily.","evidence":"Structural determination of SALSA SRCR domains with cation-binding site identification and comparative analysis","pmids":["32098784"],"confidence":"High","gaps":["Co-structures with specific bacterial/viral ligands not solved","How the cation site reconciles diverse ligand classes not shown"]},{"year":2022,"claim":"Implicated DMBT1 in tumor suppression via galectin-3/PI3K-AKT and in exosome-delivered pro-angiogenic signaling, extending its activities to growth control and tissue repair.","evidence":"Overexpression and Co-IP in ovarian cancer cells; exosome proteomics and DMBT1 knockdown in stem-cell/MSC exosomes with angiogenesis and wound-healing readouts","pmids":["32424818","29556344","35726847"],"confidence":"Low","gaps":["Galectin-3 interaction rests on single Co-IP with pharmacological pathway inference, no reconstitution","Direct binding underlying exosomal angiogenesis not demonstrated","How a secreted SRCR protein engages intracellular PI3K/AKT/beta-catenin pathways unexplained"]},{"year":null,"claim":"How a single dual-cation SRCR fold reconciles recognition of structurally diverse ligands (bacterial pili, LRR proteins, sialoglycans, gp120 V3, SP-D, complement initiators), and how the secreted/ECM hensin form transmits differentiation signals through beta1 integrin, remain mechanistically open.","evidence":"","pmids":[],"confidence":"High","gaps":["No co-crystal structures with physiological ligands","Signal transduction from hensin ECM to intracellular polarity reversal undefined","Determinants of HIV inhibition versus enhancement unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[10,13,14]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[25]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[15]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2,5]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[23]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[30,33]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,16,25]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,16,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,24]}],"complexes":[],"partners":["SFTPD","TFF3","ITGB1","LGALS3","MBL2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UGM3","full_name":"Scavenger receptor cysteine-rich domain-containing protein DMBT1","aliases":["Deleted in malignant brain tumors 1 protein","Glycoprotein 340","Gp-340","Hensin","Salivary agglutinin","SAG","Surfactant pulmonary-associated D-binding protein"],"length_aa":2413,"mass_kda":260.7,"function":"May be considered as a candidate tumor suppressor gene for brain, lung, esophageal, gastric, and colorectal cancers. May play roles in mucosal defense system, cellular immune defense and epithelial differentiation. May play a role as an opsonin receptor for SFTPD and SPAR in macrophage tissues throughout the body, including epithelial cells lining the gastrointestinal tract. May play a role in liver regeneration. May be an important factor in fate decision and differentiation of transit-amplifying ductular (oval) cells within the hepatic lineage. Required for terminal differentiation of columnar epithelial cells during early embryogenesis. May function as a binding protein in saliva for the regulation of taste sensation. Binds to HIV-1 envelope protein and has been shown to both inhibit and facilitate viral transmission. Displays a broad calcium-dependent binding spectrum against both Gram-positive and Gram-negative bacteria, suggesting a role in defense against bacterial pathogens. Binds to a range of poly-sulfated and poly-phosphorylated ligands which may explain its broad bacterial-binding specificity. Inhibits cytoinvasion of S.enterica. Associates with the actin cytoskeleton and is involved in its remodeling during regulated exocytosis. Interacts with pancreatic zymogens in a pH-dependent manner and may act as a Golgi cargo receptor in the regulated secretory pathway of the pancreatic acinar cell","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9UGM3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DMBT1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DMBT1","total_profiled":1310},"omim":[{"mim_id":"606417","title":"WD REPEAT-CONTAINING PROTEIN 11; WDR11","url":"https://www.omim.org/entry/606417"},{"mim_id":"606079","title":"CD163 ANTIGEN-LIKE 1; CD163L1","url":"https://www.omim.org/entry/606079"},{"mim_id":"601969","title":"DELETED IN MALIGNANT BRAIN TUMORS 1; DMBT1","url":"https://www.omim.org/entry/601969"},{"mim_id":"178635","title":"SURFACTANT, PULMONARY-ASSOCIATED PROTEIN D; SFTPD","url":"https://www.omim.org/entry/178635"},{"mim_id":"155255","title":"MEDULLOBLASTOMA; MDB","url":"https://www.omim.org/entry/155255"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centriolar satellite","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":1551.2},{"tissue":"salivary gland","ntpm":487.7}],"url":"https://www.proteinatlas.org/search/DMBT1"},"hgnc":{"alias_symbol":["GP340","SALSA","Gp-340"],"prev_symbol":[]},"alphafold":{"accession":"Q9UGM3","domains":[{"cath_id":"3.10.250.10","chopping":"102-202","consensus_level":"high","plddt":89.039,"start":102,"end":202},{"cath_id":"3.10.250.10","chopping":"234-334","consensus_level":"high","plddt":89.0946,"start":234,"end":334},{"cath_id":"3.10.250.10","chopping":"363-463","consensus_level":"high","plddt":87.4791,"start":363,"end":463},{"cath_id":"3.10.250.10","chopping":"503-594","consensus_level":"high","plddt":88.7155,"start":503,"end":594},{"cath_id":"3.10.250.10","chopping":"603-702","consensus_level":"high","plddt":87.5237,"start":603,"end":702},{"cath_id":"3.10.250.10","chopping":"733-833","consensus_level":"high","plddt":87.9463,"start":733,"end":833},{"cath_id":"3.10.250.10","chopping":"861-962","consensus_level":"high","plddt":88.2207,"start":861,"end":962},{"cath_id":"3.10.250.10","chopping":"992-1012_1023-1050_1065-1076_1083-1093","consensus_level":"medium","plddt":87.7121,"start":992,"end":1093},{"cath_id":"3.10.250.10","chopping":"1253-1346","consensus_level":"medium","plddt":88.1496,"start":1253,"end":1346},{"cath_id":"3.10.250.10","chopping":"1518-1612","consensus_level":"medium","plddt":84.8528,"start":1518,"end":1612},{"cath_id":"3.10.250.10","chopping":"1639-1740","consensus_level":"high","plddt":86.6953,"start":1639,"end":1740},{"cath_id":"2.60.120.290","chopping":"1770-1880","consensus_level":"medium","plddt":83.1025,"start":1770,"end":1880},{"cath_id":"3.10.250.10","chopping":"1896-1988","consensus_level":"medium","plddt":86.6087,"start":1896,"end":1988},{"cath_id":"2.60.120.290","chopping":"2007-2119","consensus_level":"high","plddt":79.04,"start":2007,"end":2119},{"cath_id":"2.60.40.3210","chopping":"2126-2252","consensus_level":"high","plddt":60.5853,"start":2126,"end":2252},{"cath_id":"2.60.40.4100","chopping":"2272-2383_2396-2403","consensus_level":"high","plddt":74.3025,"start":2272,"end":2403}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UGM3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UGM3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UGM3-F1-predicted_aligned_error_v6.png","plddt_mean":73.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DMBT1","jax_strain_url":"https://www.jax.org/strain/search?query=DMBT1"},"sequence":{"accession":"Q9UGM3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UGM3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UGM3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UGM3"}},"corpus_meta":[{"pmid":"9288095","id":"PMC_9288095","title":"DMBT1, 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\"Representational difference analysis, molecular cloning, PCR-based deletion analysis, expression analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — foundational cloning paper with multiple orthogonal methods (RDA, cloning, deletion mapping, expression analysis); independently replicated across subsequent studies\",\n      \"pmids\": [\"9288095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"gp-340 (DMBT1) was purified from human bronchioalveolar lung washings and shown to bind surfactant protein D (SP-D) in a calcium-dependent, maltose-independent manner (protein-protein interaction via the CRD of SP-D), and was localized to the surface of and within alveolar macrophages.\",\n      \"method\": \"Protein purification, calcium-dependent binding assay, inhibition with maltose, immunohistochemistry, N-glycosidase F digestion, SDS-PAGE\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct biochemical binding assay with inhibition controls, replicated by multiple subsequent studies confirming SP-D interaction\",\n      \"pmids\": [\"9153228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The primary structure of gp-340 (DMBT1) was established by molecular cloning, revealing a polypeptide of 2,413 amino acids with 13 SRCR domains, SRCR-interspersed domains, two CUB domains, a 14th SRCR domain, and a zona pellucida domain. gp-340 was confirmed to bind SP-D calcium-dependently. The protein is found in a soluble form and membrane-associated on alveolar macrophages, with SP-D and gp-340 co-localizing in the same phagosome/phagolysosome compartments.\",\n      \"method\": \"Molecular cloning (7,686-bp cDNA), RT-PCR, immunohistochemistry, co-localization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — complete cDNA cloning with domain mapping, replicated SP-D binding, functional localization in macrophage phagosomes\",\n      \"pmids\": [\"10485905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Hensin, the polarity-reversal extracellular matrix protein that converts beta-intercalated cells to alpha-intercalated cell phenotype, is an alternatively spliced product of the DMBT1 gene. Mouse genomic hensin maps to chromosome 7F4, syntenic to human 10q25-26.\",\n      \"method\": \"cDNA cloning, genomic Southern hybridization, chromosomal synteny mapping, immunoblotting with domain-specific antibodies\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — molecular cloning plus genomic mapping, independently confirmed by subsequent knockout study\",\n      \"pmids\": [\"10444583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"DMBT1 protein isoforms are identical to the collectin-binding protein gp-340 involved in respiratory immune defense; DMBT1 is expressed throughout the immune system; its orthologs CRP-ductin (mouse) and hensin (rabbit) are implicated in epithelial differentiation, indicating DMBT1 has dual functions in immune defense and epithelial development.\",\n      \"method\": \"Western blot, immunohistochemistry, RT-PCR expression analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — immunoblot identity confirmation and tissue expression, single lab, multiple methods\",\n      \"pmids\": [\"10749143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Salivary agglutinin is identical to lung gp-340 (DMBT1) as confirmed by MALDI-TOF mass spectrometry peptide sequencing and immunoblotting. Salivary agglutinin/gp-340 binds Streptococcus mutans, Helicobacter pylori, Streptococcus agalactiae, and oral commensal streptococci. The salivary form carries sialyl Le(x) carbohydrate not present on lung gp-340, indicating tissue-specific glycoforms.\",\n      \"method\": \"Protein purification, MALDI-TOF MS, HPLC peptide sequencing, immunoblotting with cross-reactive antibodies, bacterial binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mass spectrometry sequence identity plus immunoblot cross-reactivity, replicated by subsequent studies\",\n      \"pmids\": [\"11007786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Salivary agglutinin is identical to gp-340/DMBT1, confirmed by Q-TOF tandem MS peptide sequencing showing 100% identity to SRCR domain sequences of gp-340. Agglutinin and gp-340 bind S. mutans and surfactant protein D in a similar manner, and share histochemical distribution in submandibular salivary glands.\",\n      \"method\": \"Q-TOF tandem MS, Western blotting with cross-reactive monoclonal antibodies, bacterial binding assay, SP-D binding assay, immunohistochemistry\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct protein sequencing confirming identity, replicated with multiple orthogonal methods\",\n      \"pmids\": [\"11563989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The bacteria-binding domain of salivary agglutinin/DMBT1 was localized to the SRCR domains. A 16-amino-acid consensus peptide (SRCRP2: QGRVEVLYRGSWGTVC) derived from the SRCR domain was identified as the minimal bacteria-binding site, capable of binding and agglutinating S. mutans and other bacteria.\",\n      \"method\": \"Endoproteinase Lys-C digestion, synthetic consensus peptides, bacterial adhesion and agglutination assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — peptide mapping with synthetic peptides and functional binding assays; confirmed by subsequent mutagenesis studies\",\n      \"pmids\": [\"12050164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mouse CRP-ductin (the DMBT1 ortholog) binds human SP-D in a calcium-dependent, maltose-insensitive manner and shows calcium-dependent binding to both gram-positive and gram-negative bacteria, supporting a conserved role in mucosal immune defense.\",\n      \"method\": \"Protein purification, calcium-dependent binding assay, bacterial binding assay, immunoblotting, RT-PCR\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical binding assays with inhibition controls in mouse ortholog, single lab\",\n      \"pmids\": [\"12884308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The minimal bacteria-binding motif on DMBT1 was narrowed to an 11-amino-acid sequence (DMBT1pbs1: GRVEVLYRGSW) within the SRCR domains. Alanine substitution scanning revealed that VEVL and the terminal Trp are critical residues. Only DMBT1 orthologs, not other SRCR proteins, bound bacteria via this motif.\",\n      \"method\": \"Overlapping synthetic peptides, alanine substitution scanning, bacterial binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis (alanine scan) identifying critical residues, multiple bacteria tested\",\n      \"pmids\": [\"15355985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"gp340 (DMBT1) binds to the V3 loop region of HIV-1 gp120 (a linear, conserved sequence near the V3 stem critical for chemokine receptor interaction). This binding is distinct from the CD4-binding site, is enhanced by prebinding of sCD4 to gp120, and mediates inhibition of HIV-1 infection.\",\n      \"method\": \"V3 peptide binding assays, HIV-1 infection inhibition assays, sCD4 competition assay\",\n      \"journal\": \"AIDS research and human retroviruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct peptide binding and functional infection assay, single lab\",\n      \"pmids\": [\"15242536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Fluid-phase gp340 and surface-adsorbed gp340 display differential bacterial recognition: fluid-phase gp340 aggregates bacteria via antigen I/II (SspA/SspB) polypeptides of S. gordonii, while surface-bound gp340 mediates adhesion via the sialic acid-binding adhesin Hsa. Mga virulence regulator deletion in S. pyogenes increases aggregation by gp340.\",\n      \"method\": \"Bacterial aggregation and adhesion assays with purified proteins, isogenic mutants lacking specific adhesins, hydroxylapatite surface-adsorption\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mutant approach with defined adhesin deletions, multiple bacterial species, single lab\",\n      \"pmids\": [\"15784568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"DMBT1 expression in gastric epithelial cells (AGS) is regulated by ERK and PKC signaling: high ERK activity suppresses DMBT1, while ERK inhibition or high cell density (causing G0/G1 arrest) induces DMBT1. DMBT1 knockdown by siRNA reduced PMA-induced trefoil factor 1 (TFF1) induction, suggesting DMBT1 acts at an early stage of gastric epithelial differentiation.\",\n      \"method\": \"RT-PCR, siRNA knockdown, ERK inhibitor (PD98059), CFSE labeling for cell growth, flow cytometry (G0/G1 arrest analysis)\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus siRNA knockdown with defined readouts, single lab\",\n      \"pmids\": [\"15760920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The N-terminal SRCR domain of gp-340 (a 35-kDa truncated recombinant protein comprising the first SRCR and half of the first SID) is sufficient to bind HIV-1 gp120 V3 sequences in a Ca2+-dependent manner and inhibits both CCR5- and CXCR4-tropic HIV-1 isolates, similar to the full-length protein.\",\n      \"method\": \"Recombinant protein expression in 293 cells, Ca2+-dependent binding assay, HIV-1 infection inhibition assay\",\n      \"journal\": \"AIDS research and human retroviruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-deletion approach with functional assay, single lab\",\n      \"pmids\": [\"16796526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"gp340 expressed on human genital epithelial cells binds HIV-1 envelope via a specific protein-protein interaction, allowing otherwise subinfectious amounts of HIV to efficiently infect target cells and extending the duration of viral infectivity.\",\n      \"method\": \"Cell surface expression analysis, HIV binding assays, HIV infection assays with blocking antibodies/peptides\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — blocking antibodies/peptides confirming specific interaction mechanism, single lab\",\n      \"pmids\": [\"17709527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DMBT1 is a target gene of the intracellular pathogen receptor NOD2 via NF-κB activation in intestinal epithelial cells. TNF-α and LPS up-regulate DMBT1 expression. DMBT1 inhibits Salmonella enterica cytoinvasion and suppresses LPS- and muramyl dipeptide-induced NF-κB activation and cytokine secretion in vitro.\",\n      \"method\": \"In vitro stimulation, NF-κB reporter assay, siRNA knockdown, bacterial invasion assay, cytokine ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate–Strong — multiple orthogonal methods (NF-κB reporter, bacterial invasion assay, cytokine measurement, NOD2 mutant patient tissue), single lab but comprehensive\",\n      \"pmids\": [\"17548659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Dmbt1-deficient mice display enhanced susceptibility to dextran sulfate sodium-induced colitis with elevated Tnf, Il6, and Nod2 expression, demonstrating that DMBT1 confers mucosal protection in vivo. A deletion allele of DMBT1 with reduced SRCR domain-coding exons is associated with increased Crohn's disease risk.\",\n      \"method\": \"Dmbt1-/- knockout mice, DSS-induced colitis model, qRT-PCR, immunohistochemistry, genetic association study\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse model with defined phenotype plus human genetic association, replicated finding\",\n      \"pmids\": [\"17983803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"gp340 aggregates Group A streptococci by binding GAS pili. Pilus-defective GAS mutants fail to aggregate in saliva and show reduced gp340 binding. Heterologous expression of GAS pili on Lactococcus lactis confers gp340-mediated aggregation. gp340-mediated aggregation reduces bacterial adhesion to human epithelial cells.\",\n      \"method\": \"Pilus-defective GAS mutants, heterologous pilus expression, purified gp340 aggregation assay, bacterial adhesion assay\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — isogenic mutants and heterologous expression reconstituting phenotype, functional adhesion readout\",\n      \"pmids\": [\"18452511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A common bacteria-binding motif RVEVLYxxxSW within DMBT1 SRCR domains mediates binding of a broad range of bacteria. Alanine substitution scanning of SRCRP2 showed that 8 residues are involved in binding with species-specific variation, but the core VxVxY and W residues are always required.\",\n      \"method\": \"Alanine substitution peptide scan, bacterial adhesion and agglutination assays with multiple species\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — systematic mutagenesis with functional assays across multiple bacterial species, single lab\",\n      \"pmids\": [\"18713006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Monocyte-derived macrophages express gp340, and HIV-1 infection of macrophages is decreased when the viral envelope cannot bind gp340. Inhibition occurred at the level of membrane fusion for M-, T-, and dual-tropic envelopes, suggesting gp340 enhances HIV-1 infection of macrophages by concentrating virus locally.\",\n      \"method\": \"Macrophage expression analysis, HIV infection inhibition with anti-gp340 antibodies/peptides blocking envelope binding, fusion assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — blocking antibody approach with specific fusion-level readout, single lab\",\n      \"pmids\": [\"18641344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Muclin (Dmbt1 product) deficiency in mice impairs exocrine pancreatic function: attenuated neurohormonal-stimulated amylase release from acinar cells and retarded trafficking of newly synthesized secretory proteins to the stimulus-releasable pool, as shown by pulse-chase analysis.\",\n      \"method\": \"Dmbt1-/- knockout mice, amylase release assay, [35S]Met/Cys pulse-chase protein trafficking analysis\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse model with defined biochemical phenotype (pulse-chase), single lab\",\n      \"pmids\": [\"18202109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"gp340 mediates transcytosis of HIV-1 across genital tract-derived cell lines and primary endocervical tissue from apical to basolateral surfaces. This transcytosis is blocked by antibodies or peptides that disrupt gp340-HIV envelope interaction. Heparan sulfate moieties on gp340 also participate in mediating transcytosis.\",\n      \"method\": \"Transwell transcytosis assay with primary endocervical tissue, blocking antibodies/peptides, heparan sulfate perturbation\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary tissue model with specific blocking reagents, single lab\",\n      \"pmids\": [\"19553331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Leucine-rich repeat (Lrr) motifs on bacterial surface proteins (S. pyogenes Spy0843, S. agalactiae LrrG, T. forsythia BspA) serve as recognition motifs for human gp340/DMBT1. The Lrr region mediates binding to gp340, and VEVLXXXXW-containing peptides inhibit this binding, implicating a gp340 core peptide distinct from the XXXXW motif.\",\n      \"method\": \"Mass spectrometry sequencing, gene inactivation (bacterial mutants), recombinant truncated protein binding assay, peptide inhibition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and recombinant protein approach with multiple bacterial species, single lab\",\n      \"pmids\": [\"19465482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Deletion of hensin/DMBT1 from intercalated cells blocks conversion of beta- to alpha-intercalated cells in the renal collecting tubule, causing complete distal renal tubular acidosis (dRTA). Polymerization and ECM deposition of hensin requires beta1 integrin activation; conditional deletion of beta1 integrin from intercalated cells produces an identical phenotype.\",\n      \"method\": \"Conditional Dmbt1 knockout and beta1-integrin knockout mice, immunofluorescence localization of V-ATPase/pendrin/kAE1, acid-feeding challenge, electron microscopy\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent conditional knockout models with identical phenotype, mechanistic epistasis (hensin requires beta1 integrin), multiple orthogonal readouts\",\n      \"pmids\": [\"21098262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DMBT1 expression in intestinal epithelial cells is induced by IL-22 through STAT3 tyrosine phosphorylation and NF-κB activation. The IL-22-responsive element was mapped to positions -187 to -179 in the DMBT1 promoter by deletion analysis and EMSA.\",\n      \"method\": \"Microarray, siRNA knockdown of STAT3, MEK/PI3K/NF-κB inhibitors, promoter deletion luciferase assay, EMSA\",\n      \"journal\": \"Inflammatory bowel diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mapping by deletion and EMSA, pathway inhibitors with siRNA, single lab\",\n      \"pmids\": [\"20824812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Salivary agglutinin (DMBT1) activates complement via the lectin pathway (MBL pathway): antibodies against mannose-binding lectin (MBL) block C4 deposition on SAG-coated plates, SAG induces no C4 deposition in MBL-deficient sera, and periodate treatment of SAG (removing carbohydrate) abolishes MBL pathway activation.\",\n      \"method\": \"C4 deposition ELISA on SAG-coated microplates, MBL-blocking antibodies, MBL-deficient sera, periodate carbohydrate oxidation\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic complement pathway assignment using pathway-specific deficient sera and glycan perturbation, single lab\",\n      \"pmids\": [\"21920605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Staphylococcus aureus surface protein SasA is responsible for binding to gp340/DMBT1. Inactivation of the sasA gene reduces S. aureus binding to gp340-coated surfaces. Recombinant SasA binds gp340, inhibited by N-acetylneuraminic acid; surface plasmon resonance shows rSasA binds NeuAcα(2-3)Galβ(1-4)GlcNAc structures on gp340.\",\n      \"method\": \"Gene inactivation (sasA mutant), recombinant protein binding assay, sialic acid inhibition, surface plasmon resonance\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — genetic mutant plus recombinant protein SPR with defined carbohydrate inhibition, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23439307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DMBT1(gp340) binds to solid-phase dimeric TFF3 in a calcium-dependent manner but does not bind monomeric TFF3, TFF2, or glycosylated TFF2, establishing a specific interaction requiring TFF3 dimerization.\",\n      \"method\": \"ELISA-based binding assay with recombinant TFF isoforms, calcium dependency analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding ELISA with defined isoform specificity controls and calcium dependency, single lab\",\n      \"pmids\": [\"23691218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The non-coding DMBT1 SNP rs2981804 modifies DNA binding sites for transcription factors CREB1 and ATF-2, and the genomic region comprising rs2981804 acts as a transcriptional regulator in vitro; the CD risk allele is associated with decreased intestinal DMBT1 expression. IL-22 induces DMBT1 expression in intestinal epithelial cells via STAT3, ATF-2, and CREB1.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), luciferase reporter assay, siRNA knockdown, quantitative PCR, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and luciferase assay with siRNA confirmation, single lab, multiple methods\",\n      \"pmids\": [\"24223725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DMBT1 purified from human saliva inhibits twitching motility of Pseudomonas aeruginosa and prevents bacterial traversal of human corneal epithelial cells in vitro and reduces disease in a murine corneal infection model. DMBT1 does not affect PilA expression or intracellular cAMP levels, but dot-immunoblot assays show purified DMBT1 directly binds P. aeruginosa pili, suggesting inhibition involves a direct pili interaction.\",\n      \"method\": \"Protein fractionation and mass spectrometry identification, immunoprecipitation, purified DMBT1 twitching assay, dot-immunoblot pili binding assay, epithelial cell traversal assay, murine corneal infection model\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification, direct pili binding assay, in vivo model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28489917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DMBT1 protein is enriched in exosomes from human urine-derived stem cells (USC-Exos) and is required for USC-Exos-induced promotion of angiogenic responses of endothelial cells in vitro and for angiogenesis and wound healing in diabetic mice in vivo.\",\n      \"method\": \"Exosome proteomics, DMBT1 knockdown in USC-Exos, in vitro angiogenesis assays, streptozotocin-induced diabetic mouse wound healing model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function knockdown in exosome context with in vitro and in vivo readouts, single lab\",\n      \"pmids\": [\"29556344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal/structural analysis of DMBT1 (SALSA) SRCR domains 1 and 8 revealed a novel universal ligand-binding mechanism: the binding interface incorporates a dual cation-binding site that is highly conserved across the SRCR superfamily, suggesting this mechanism is applicable to all SRCR domains.\",\n      \"method\": \"Structural determination (crystallography implied), cation-binding site identification, comparative analysis across SRCR superfamily\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural determination with functional validation of binding mechanism, single lab\",\n      \"pmids\": [\"32098784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DMBT1 overexpression in ovarian cancer cells inhibits proliferation, migration, and invasion, and immunoprecipitation reveals a direct interaction between DMBT1 and galectin-3. DMBT1 decreases galectin-3 expression and inhibits PI3K/AKT phosphorylation; overexpression of galectin-3 reverses DMBT1-mediated tumor suppression.\",\n      \"method\": \"Overexpression, CCK-8 proliferation assay, wound healing/transwell invasion assay, immunoprecipitation, Western blot for PI3K/AKT phosphorylation\",\n      \"journal\": \"Cell biochemistry and function\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with pharmacological pathway inference, single lab, no rescue or reconstitution\",\n      \"pmids\": [\"32424818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Exosomes derived from MSCs pretreated with ischemic heart extracts contain elevated DMBT1; silencing DMBT1 in MSCs reduces DMBT1 in exosomes and impairs HUVEC proliferation and migration, along with decreased p-Akt, beta-catenin, and VEGF, suggesting DMBT1 delivery via exosomes promotes angiogenesis through Akt/beta-catenin/VEGF signaling.\",\n      \"method\": \"Proteomics, DMBT1 siRNA knockdown, MTT and wound healing assays, Western blot for pathway components\",\n      \"journal\": \"Cell transplantation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, siRNA knockdown with pathway Western blot but no reconstitution or direct binding confirmation\",\n      \"pmids\": [\"35726847\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DMBT1 (also known as gp-340, SALSA, salivary agglutinin, and hensin) is a large, multi-domain scavenger receptor cysteine-rich (SRCR) secreted glycoprotein that functions as a broad-spectrum pattern recognition molecule at mucosal surfaces: its conserved SRCR domain VEVLXXXXW motif directly binds bacterial pili, surface proteins (including LRR-containing proteins), and other pathogen-associated structures to agglutinate and clear bacteria; via its SRCR domains it also binds HIV-1 gp120 at the V3 loop in a calcium-dependent manner to inhibit or facilitate infection depending on cell context; it interacts with surfactant proteins A and D, IgA, lactoferrin, complement initiators (C1q, MBL, ficolins), and dimeric TFF3 through its SRCR domains and associated glycans; its structural basis involves a dual cation-binding site in SRCR domains that mediates ligand binding conserved across the SRCR superfamily; as hensin/DMBT1, its ECM polymerization (requiring beta1-integrin activation) drives terminal differentiation of renal intercalated cells from HCO3-secreting (beta) to acid-secreting (alpha) phenotype; its expression is regulated by NOD2/NF-κB, IL-22/STAT3/NF-κB, and ERK signaling; and it promotes angiogenesis when delivered via exosomes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DMBT1 is a large, multi-domain scavenger receptor cysteine-rich (SRCR) glycoprotein that functions as a broad-spectrum pattern-recognition molecule at mucosal surfaces and, in an alternatively spliced/orthologous form (hensin/CRP-ductin/muclin), as an extracellular matrix regulator of epithelial differentiation [#0, #2, #3, #4]. The protein — independently characterized as lung gp-340 and salivary agglutinin and shown by mass spectrometry to be identical — comprises 13–14 SRCR domains interspersed with SID and CUB domains and a terminal zona pellucida domain [#2, #5, #6]. Its bacteria-binding activity maps to a conserved SRCR motif: peptide and alanine-scanning studies narrowed the minimal site to an 11-residue sequence (GRVEVLYRGSW) within which the core VEVL and terminal tryptophan are critical, defining a common RVEVLYxxxSW recognition motif that binds a broad range of bacteria including S. mutans, group A streptococci, and S. aureus [#7, #9, #18]. Through these SRCR domains DMBT1 recognizes bacterial pili, antigen I/II polypeptides, leucine-rich-repeat surface proteins (Spy0843, LrrG, BspA), and the sialoadhesin SasA, agglutinating bacteria and reducing their epithelial adhesion [#11, #17, #22, #26, #29]. A dual cation-binding site within the SRCR fold provides the structural basis for this conserved ligand recognition [#31]. DMBT1 also binds surfactant protein D calcium-dependently and co-localizes with it in macrophage phagosomes, and it activates complement via the MBL/lectin pathway through its carbohydrate moieties [#1, #2, #25]. In innate immune signaling it is a NOD2/NF-\\u03baB and IL-22/STAT3 target gene that dampens LPS- and muramyl-dipeptide-induced NF-\\u03baB activation and confers mucosal protection: Dmbt1-deficient mice show enhanced DSS colitis and a reduced-SRCR deletion allele is associated with Crohn's disease risk [#15, #16, #24]. As hensin, DMBT1 polymerization and ECM deposition — requiring beta1-integrin activation — drives terminal differentiation of renal intercalated cells, and its loss causes complete distal renal tubular acidosis [#23]. It binds HIV-1 gp120 at the V3 loop in a calcium-dependent manner through its N-terminal SRCR domain, an interaction that inhibits infection in some contexts yet promotes viral capture, transcytosis, and infection of mucosal target cells in others [#10, #13, #14, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established DMBT1 as a candidate tumor-suppressor gene of the SRCR superfamily, defining its genomic locus and linking its loss to brain malignancy.\",\n      \"evidence\": \"Representational difference analysis, cloning, and deletion mapping in medulloblastoma/glioblastoma lines and tumors\",\n      \"pmids\": [\"9288095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No protein-level function defined at this stage\", \"Causality of deletions in tumorigenesis not tested by rescue\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identified the secreted/macrophage-associated protein gp-340 and its calcium-dependent SP-D interaction, situating DMBT1 in respiratory innate defense before the gp-340/DMBT1 identity was formalized.\",\n      \"evidence\": \"Protein purification from lung washings, calcium-dependent maltose-insensitive SP-D binding, immunohistochemistry\",\n      \"pmids\": [\"9153228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full primary structure and domain architecture not yet known\", \"Physiological consequence of SP-D binding not established\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved the complete domain architecture (13+1 SRCR, SID, CUB, ZP domains) and unified gp-340 with the renal differentiation factor hensin as DMBT1 splice products, revealing dual immune and epithelial roles.\",\n      \"evidence\": \"cDNA cloning, domain mapping, genomic synteny mapping, immunoblotting\",\n      \"pmids\": [\"10485905\", \"10444583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which domains mediate which functions not yet mapped\", \"Splice-isoform tissue distribution incompletely defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Mass-spectrometric identity established that salivary agglutinin, lung gp-340, and DMBT1 are the same molecule with tissue-specific glycoforms, explaining its broad bacterial-binding reputation across mucosa.\",\n      \"evidence\": \"MALDI-TOF/Q-TOF peptide sequencing, immunoblot cross-reactivity, bacterial binding assays\",\n      \"pmids\": [\"11007786\", \"11563989\", \"10749143\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of tissue-specific glycans not dissected\", \"Binding domain not yet localized\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Localized bacterial recognition to the SRCR domains and defined a minimal binding peptide, converting a multi-domain protein into a tractable molecular recognition unit.\",\n      \"evidence\": \"Proteolytic mapping plus synthetic SRCRP2 consensus peptide binding/agglutination assays\",\n      \"pmids\": [\"12050164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Individual critical residues not yet identified\", \"Structural basis of peptide-ligand contact unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mutagenesis pinpointed VEVL and the terminal Trp as essential and showed only DMBT1 orthologs use this motif, defining the chemistry of broad bacterial recognition.\",\n      \"evidence\": \"Overlapping peptides and alanine-substitution scanning with bacterial binding assays\",\n      \"pmids\": [\"15355985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bacterial counter-ligands for many species still unknown\", \"Whether motif binds protein or glycan ligands not resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated DMBT1 binds the conserved HIV-1 gp120 V3 loop independently of the CD4 site and inhibits infection, extending its pattern recognition to a virus.\",\n      \"evidence\": \"V3 peptide binding, sCD4 competition, HIV infection inhibition assays\",\n      \"pmids\": [\"15242536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependence of inhibition versus enhancement unresolved\", \"Domain responsible not yet mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed fluid-phase versus surface-adsorbed DMBT1 recognize bacteria via distinct adhesins, establishing that immobilization state dictates recognition outcome (aggregation versus adhesion).\",\n      \"evidence\": \"Aggregation/adhesion assays with isogenic adhesin mutants and surface adsorption\",\n      \"pmids\": [\"15784568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural change upon surface adsorption not defined\", \"Single bacterial genus tested for the mechanism\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Positioned DMBT1 within innate immune signaling as a NOD2/NF-\\u03baB target that feedback-suppresses NF-\\u03baB and limits bacterial invasion, and demonstrated in vivo mucosal protection with a human Crohn's disease association.\",\n      \"evidence\": \"NF-\\u03baB reporters, siRNA, Salmonella invasion assays; Dmbt1-/- DSS colitis model and genetic association\",\n      \"pmids\": [\"17548659\", \"17983803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which DMBT1 dampens NF-\\u03baB signaling not defined\", \"Causal SRCR-deletion variant biology in patients incomplete\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Refined the universal bacterial-binding motif (RVEVLYxxxSW) with species-specific residue usage and linked DMBT1 deficiency to impaired pancreatic exocrine secretory trafficking, broadening its functional scope.\",\n      \"evidence\": \"Alanine scan across multiple species; Dmbt1-/- pancreatic amylase release and pulse-chase trafficking\",\n      \"pmids\": [\"18713006\", \"18202109\", \"18452511\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a secreted SRCR protein influences intracellular secretory trafficking unclear\", \"Direct pili counter-receptor structure not solved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the dual HIV outcome by showing genital/macrophage DMBT1 concentrates virus, enhances fusion, and mediates apical-to-basolateral transcytosis, reframing it as a context-dependent infection facilitator.\",\n      \"evidence\": \"Macrophage/genital epithelial infection and fusion assays, transwell transcytosis with primary endocervical tissue, blocking reagents, heparan sulfate perturbation\",\n      \"pmids\": [\"18641344\", \"17709527\", \"19553331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"What determines inhibition versus enhancement in vivo unknown\", \"Relative contribution of SRCR versus heparan sulfate moieties unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified bacterial leucine-rich-repeat surface proteins as a recurring class of DMBT1 ligands, implicating a core peptide distinct from the XXXXW motif.\",\n      \"evidence\": \"Mass spectrometry, bacterial gene inactivation, recombinant truncated protein and peptide inhibition assays\",\n      \"pmids\": [\"19465482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural mapping of the LRR-binding core peptide not done\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the hensin/DMBT1 differentiation mechanism: beta1-integrin-dependent ECM polymerization converts beta- to alpha-intercalated cells, and its loss causes complete distal renal tubular acidosis.\",\n      \"evidence\": \"Conditional Dmbt1 and beta1-integrin knockout mice, V-ATPase/pendrin/kAE1 immunofluorescence, acid-feeding challenge\",\n      \"pmids\": [\"21098262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between ECM polymerization and intracellular polarity reversal not defined\", \"Receptor downstream of beta1 integrin not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapped IL-22/STAT3-NF-\\u03baB and CREB1/ATF-2 transcriptional control of DMBT1 and tied a non-coding risk SNP to reduced intestinal expression, connecting cytokine signaling to mucosal defense capacity.\",\n      \"evidence\": \"Microarray, STAT3 siRNA, pathway inhibitors, promoter deletion luciferase, EMSA\",\n      \"pmids\": [\"20824812\", \"24223725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative effect of expression on host protection not measured\", \"In vivo relevance of the SNP regulation not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed DMBT1 activates the lectin (MBL) complement pathway through its carbohydrate, linking pattern recognition to complement-mediated clearance.\",\n      \"evidence\": \"C4 deposition ELISA with MBL-blocking antibodies, MBL-deficient sera, periodate glycan oxidation\",\n      \"pmids\": [\"21920605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the MBL-engaging glycan not defined\", \"Downstream opsonization/clearance not measured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expanded the ligand repertoire with the S. aureus sialoadhesin SasA and dimeric TFF3, both engaged via defined carbohydrate or dimerization-dependent contacts.\",\n      \"evidence\": \"sasA inactivation, SPR with defined sialyl glycans; ELISA binding with TFF isoform controls\",\n      \"pmids\": [\"23439307\", \"23691218\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of TFF3 binding not established\", \"In vivo relevance of SasA interaction untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated DMBT1 directly binds Pseudomonas aeruginosa pili to inhibit twitching motility and corneal traversal in vivo, showing motility/virulence suppression beyond simple agglutination.\",\n      \"evidence\": \"Mass spectrometry identification, dot-immunoblot pili binding, twitching and epithelial traversal assays, murine corneal infection model\",\n      \"pmids\": [\"28489917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which pili binding inhibits motility unresolved\", \"PilA/cAMP shown unaffected, leaving signaling step unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the structural basis for DMBT1 ligand recognition: a dual cation-binding site in SRCR domains 1 and 8 conserved across the SRCR superfamily.\",\n      \"evidence\": \"Structural determination of SALSA SRCR domains with cation-binding site identification and comparative analysis\",\n      \"pmids\": [\"32098784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-structures with specific bacterial/viral ligands not solved\", \"How the cation site reconciles diverse ligand classes not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated DMBT1 in tumor suppression via galectin-3/PI3K-AKT and in exosome-delivered pro-angiogenic signaling, extending its activities to growth control and tissue repair.\",\n      \"evidence\": \"Overexpression and Co-IP in ovarian cancer cells; exosome proteomics and DMBT1 knockdown in stem-cell/MSC exosomes with angiogenesis and wound-healing readouts\",\n      \"pmids\": [\"32424818\", \"29556344\", \"35726847\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Galectin-3 interaction rests on single Co-IP with pharmacological pathway inference, no reconstitution\", \"Direct binding underlying exosomal angiogenesis not demonstrated\", \"How a secreted SRCR protein engages intracellular PI3K/AKT/beta-catenin pathways unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single dual-cation SRCR fold reconciles recognition of structurally diverse ligands (bacterial pili, LRR proteins, sialoglycans, gp120 V3, SP-D, complement initiators), and how the secreted/ECM hensin form transmits differentiation signals through beta1 integrin, remain mechanistically open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structures with physiological ligands\", \"Signal transduction from hensin ECM to intracellular polarity reversal undefined\", \"Determinants of HIV inhibition versus enhancement unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [10, 13, 14]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [25]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2, 5]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [30, 33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 16, 25]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 16, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SFTPD\", \"TFF3\", \"ITGB1\", \"LGALS3\", \"MBL2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}