{"gene":"MUC5AC","run_date":"2026-06-10T05:19:51","timeline":{"discoveries":[{"year":2005,"finding":"Dual oxidase 1 (Duox1) generates reactive oxygen species that activate TACE (TNF-alpha-converting enzyme), leading to cleavage of pro-TGF-alpha and subsequent EGFR activation, resulting in MUC5AC expression in airway epithelial cells. PKCdelta/PKC lies upstream of Duox1 in this cascade.","method":"siRNA knockdown of Duox1, ROS scavengers, NADPH oxidase inhibitors, TACE inhibition; stimulation with PMA and neutrophil elastase in human bronchial epithelial cells and NCI-H292 cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, pharmacologic inhibitors, ROS measurement) in two cell models, pathway validated at multiple nodes","pmids":["15640347"],"is_preprint":false},{"year":2009,"finding":"IL-1beta and IL-17A induce MUC5AC expression via NF-kappaB-dependent transcriptional activation. A critical NF-kappaB binding site at position -3594/-3582 in the MUC5AC promoter was identified, and chromatin immunoprecipitation confirmed enhanced binding of NF-kappaB subunit p50 to this region following cytokine stimulation.","method":"Reporter gene assay, siRNA knockdown of p65, NF-kappaB small molecule inhibitor, ChIP analysis in well-differentiated primary normal human bronchial epithelial cells and HBE1 cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — promoter reporter assay + ChIP + siRNA knockdown, multiple orthogonal methods in two cell models","pmids":["19841186"],"is_preprint":false},{"year":2007,"finding":"In allergic mouse airways, Muc5ac is the predominant gel-forming mucin induced, localizing to bronchial Clara cells. SMAD4 and HIF-1alpha bind to evolutionarily conserved motifs in the Muc5ac promoter and are required for promoter function; mutation of their recognition motifs abolishes promoter activity.","method":"Murine OVA model, luciferase reporter gene assay with promoter mutations, transcription factor binding analysis in transformed Clara cell line","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reporter assay with mutagenesis + in vivo model, multiple methods establishing both in vivo relevance and molecular mechanism","pmids":["17463395"],"is_preprint":false},{"year":2004,"finding":"The Cys subdomains of MUC5AC (Cys1 and Cys5) undergo C-mannosylation at their WXXW motifs in the endoplasmic reticulum. Mutation of the first tryptophan in the WXXW motif or expression in C-mannosylation-defective CHO-Lec35.1 cells reduces secretion and causes ER retention, indicating C-mannosylation is required for proper folding and/or ER export of MUC5AC.","method":"Pulse-chase labeling, mutagenesis of WXXW motif, lectin binding assays, live cell imaging of GFP-tagged Cys subdomains, C-mannosylation-defective cell line (CHO-Lec35.1)","journal":"Glycobiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including mutagenesis, defective cell line, pulse-chase, and live imaging, all converging on the same mechanistic conclusion","pmids":["14718370"],"is_preprint":false},{"year":2002,"finding":"IL-1beta induces MUC5AC expression in NCI-H292 airway epithelial cells through a COX-2/PGE2 pathway, with ERK1/2 and p38 MAPK acting upstream of COX-2 induction.","method":"Selective COX-2 inhibitor (NS398), MAPK inhibitors (PD98059, SB203580), exogenous PGE2 addition; mRNA and protein quantification","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic pathway dissection with multiple inhibitors in single cell line, no genetic knockdown validation","pmids":["12391274"],"is_preprint":false},{"year":2000,"finding":"Neutrophil elastase induces MUC5AC gene expression through an oxidant-dependent mechanism involving reactive oxygen species (hydroxyl radical/peroxynitrite) in airway epithelial cells.","method":"ROS scavenger DMTU, intracellular redox indicator dichlorodihydrofluorescein in A549 and primary normal human bronchial epithelial cells","journal":"Chest","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic inhibition confirmed in two cell types, single lab","pmids":["10843967"],"is_preprint":false},{"year":2007,"finding":"NQO1 (NAD(P)H:quinone oxidoreductase 1) mediates neutrophil elastase-induced oxidant stress and MUC5AC mRNA expression in airway epithelial cells; siRNA knockdown of NQO1 abrogates MUC5AC expression and reduces NE-induced lipid peroxidation.","method":"Pharmacologic NQO1 inhibitor (dicumarol), siRNA knockdown of NQO1, lipid peroxidation assay in A549 cells and primary normal human bronchial epithelial cells","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both pharmacologic inhibition and siRNA knockdown in two cell types, single lab","pmids":["17395013"],"is_preprint":false},{"year":2011,"finding":"Aspergillus fumigatus serine protease activity activates TACE, which cleaves membrane-bound pro-TGF-alpha; this leads to EGFR activation and induction of MUC5AC expression in airway epithelial cells. Cysteine protease inhibition had no effect, only serine protease inhibition blocked TACE activation and MUC5AC induction.","method":"Serine/cysteine protease inhibitors, TACE inhibitors, TACE siRNA, EGFR/TGF-alpha neutralizing antibodies in NCI-H292 cells and primary airway epithelial cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (protease inhibitors, siRNA, neutralizing antibodies) in two cell types establishing sequential pathway","pmids":["21685325"],"is_preprint":false},{"year":2009,"finding":"Neuregulin 1beta1 (NRG1beta1) induces MUC5AC and MUC5B expression in primary human bronchial epithelial cells via ErbB2 and ErbB3 receptors (not ErbB4), with downstream involvement of p38 MAPK, ERK1/2, and PI3K, and induction of ErbB2, AKT, and ERK1/2 phosphorylation.","method":"ErbB receptor-specific inhibitors, kinase inhibitors (p38, ERK1/2, PI3K), Western blot for phosphorylation, time- and dose-response studies in primary HBECs and in vivo antigen-challenged mice","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic pathway dissection with multiple inhibitors, receptor specificity tested, validated in vivo, single lab","pmids":["19556605"],"is_preprint":false},{"year":2009,"finding":"PGF2alpha induces MUC5AC overproduction in human tracheobronchial epithelial cells via a sequential signaling cascade: PKC → ERK → p90RSK → CREB. CREB directly interacts with the MUC5AC promoter via a cAMP response element, and suppression of each signaling molecule along this pathway abrogates MUC5AC expression.","method":"Pathway inhibitors, promoter reporter assay (CRE-dependent MUC5AC promoter activity), CREB-MUC5AC promoter interaction assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter + pathway inhibitor cascade, single lab","pmids":["19201889"],"is_preprint":false},{"year":2010,"finding":"Muscarinic M3 receptor (not M2) mediates carbachol-induced MUC5AC expression in human airway epithelial cells via EGFR transactivation and p44/42 MAPK phosphorylation; aclidinium inhibits carbachol- and cigarette smoke-induced MUC5AC overexpression through this pathway.","method":"siRNA against muscarinic receptor subtypes (M2, M3), EGFR tyrosine kinase inhibitor AG1478, phospho-EGFR and phospho-MAPK Western blot, in human bronchial tissue and cultured epithelial cells","journal":"The European respiratory journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor subtype identified by siRNA knockdown + pharmacologic inhibition in two tissue/cell settings, single lab","pmids":["20525722"],"is_preprint":false},{"year":2011,"finding":"EGF-induced MUC5AC expression requires bidirectional signaling between EGFR and Notch pathways: EGFR induces Notch intracellular domain (NICD) generation in an RBP-Jkappa-dependent manner, and Notch signaling amplifies EGFR/ERK activation. Forced NICD expression alone is sufficient to induce MUC5AC via EGFR-ERK activation.","method":"gamma-secretase inhibitors, Notch1 siRNA, NICD overexpression, EGFR antagonist antibody, EGFR and ERK inhibitors in NCI-H292 cells and primary human bronchial epithelial cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (siRNA, overexpression) and pharmacologic approaches in two cell types, single lab","pmids":["21622856"],"is_preprint":false},{"year":2013,"finding":"Neutrophil elastase induces MUC5AC secretion via PAR2 (protease-activated receptor 2), which increases cytosolic calcium from ER stores and via store-operated calcium entry (SOCE) channels, subsequently activating PKC to stimulate secretion.","method":"PAR1/2/3 expression analysis, PAR2 expression measurement after NE, calcium measurement with thapsigargin (ER depletion) and 2-APB (SOCE inhibitor), PKC activation assay in Calu-3 cells","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic dissection of calcium pathway with multiple inhibitors, single cell line, single lab","pmids":["23392769"],"is_preprint":false},{"year":2016,"finding":"IL-13 induces MUC5AC expression in human airway epithelial cells via STAT6-dependent upregulation of TMEM16A, whose chloride channel activity activates ERK1/2; TMEM16A knockdown or channel inhibition reduces ERK1/2 phosphorylation and MUC5AC expression.","method":"STAT6 inhibition, TMEM16A siRNA knockdown, chloride channel inhibitor T16Ainh-A01, ERK1/2 inhibitor PD98059, mRNA and protein quantification in HBE16 cells","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA + pharmacologic inhibition at multiple pathway nodes, single cell line, single lab","pmids":["27588910"],"is_preprint":false},{"year":2014,"finding":"IL-17A induces MUC5AC expression and goblet cell hyperplasia through the Act1-mediated signaling pathway involving MAPK (ERK, p38, JNK) activation; siRNA knockdown of IL-17RA, IL-17RC, and Act1 each block IL-17A-induced MUC5AC production.","method":"siRNA knockdown of IL-17RA, IL-17RC, Act1; MAPK Western blot; qPCR and Western blot in polyp epithelial cells and NCI-H292 cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple siRNA targets validating sequential pathway, two cell systems, single lab","pmids":["24892823"],"is_preprint":false},{"year":2017,"finding":"IL-1beta upregulates Muc5ac expression via NF-kappaB-induced HIF-1alpha: NF-kappaB activation induces HIF-1alpha, which directly binds the Muc5ac promoter and enhances its transcriptional activity. HIF-1alpha siRNA knockdown and NF-kappaB inhibition (Bay11-7082) each reduce IL-1beta-induced Muc5ac expression.","method":"siRNA knockdown of HIF-1alpha, NF-kappaB inhibitor, luciferase reporter assay with Muc5ac promoter, EMSA for HIF-1alpha binding to Muc5ac promoter in NHBECs","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter + EMSA + siRNA knockdown in primary cells, single lab","pmids":["29031476"],"is_preprint":false},{"year":2017,"finding":"Lyn kinase negatively regulates MUC5AC expression by downregulating STAT6 and its binding to the Muc5ac promoter; Lyn overexpression decreases IL-4/IL-13-induced MUC5AC expression and STAT6 phosphorylation, while Lyn knockdown increases them. ChIP confirmed that Lyn overexpression decreases STAT6 binding to the Muc5ac promoter.","method":"Lyn overexpression and siRNA knockdown in 16HBE cells and OVA mouse model, ChIP analysis for STAT6 binding to Muc5ac promoter, STAT6 phosphorylation Western blot","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP + gain/loss of function in vitro and in vivo, single lab","pmids":["28205598"],"is_preprint":false},{"year":2021,"finding":"Benzo(a)pyrene induces MUC5AC expression through an AhR/mitochondrial ROS/ERK pathway: AhR nuclear translocation activates CYP1s (CYP1A1/CYP1B1), increasing mitochondrial ROS, which activates ERK and CREB to drive MUC5AC promoter activity. AhR overexpression enhances and AhR/CREB siRNA knockdown reduces BaP-induced MUC5AC.","method":"AhR siRNA and overexpression lentivirus, CREB siRNA, CYP1 inhibitor, mitochondrial ROS inhibitor Mito-TEMP, ERK inhibitor U0126, luciferase MUC5AC promoter assay in NCI-H292 cells","journal":"Ecotoxicology and environmental safety","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple siRNA targets + pharmacologic inhibitors + promoter reporter, single cell line, single lab","pmids":["33421718"],"is_preprint":false},{"year":2009,"finding":"dsRNA (poly(I:C)) synergistically amplifies TGF-alpha-induced MUC5AC expression via sustained ERK activation; this occurs through poly(I:C)-mediated inhibition of MKP3 (MAPK phosphatase 3) upregulation. Overexpression of MKP3 completely suppresses the poly(I:C)-enhanced MUC5AC induction.","method":"MEK1/2 inhibitor U0126, MKP3 overexpression, ERK phosphorylation Western blot, MUC5AC promoter activity assay in NCI-H292 cells and primary HBECs","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MKP3 overexpression rescue experiment + pharmacologic inhibition in two cell types, single lab","pmids":["19109160"],"is_preprint":false},{"year":2018,"finding":"TGF-beta3 induces MUC5AC hyper-expression in airway epithelium through autophagy activation and subsequent AP-1 (activator protein-1) activation; Smad2/3 pathway mediates TGF-beta3-induced autophagy. Inhibition of autophagy reduces TGF-beta3-induced MUC5AC expression in vitro and in vivo.","method":"Autophagy inhibitors in OVA mouse model, autophagy induction by TGF-beta3 in human bronchial epithelial cells, AP-1 activation measurement, Smad2/3 pathway analysis","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — autophagy inhibition in vivo and in vitro with pathway analysis, single lab","pmids":["29997053"],"is_preprint":false},{"year":2020,"finding":"MUC5AC physically interacts with CD44 (co-immunoprecipitation), and this interaction activates Src signaling. MUC5AC knockout (CRISPR/Cas9) reduces colorectal cancer invasion/migration, increases apoptosis, and sensitizes cells to 5-FU and oxaliplatin via modulation of p53/p21/beta-catenin/CD44/Lgr5 signaling.","method":"CRISPR/Cas9 knockout, siRNA knockdown, co-immunoprecipitation, in vitro functional assays, in vivo orthotopic mouse models in CRC cell lines","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing MUC5AC-CD44 interaction + CRISPR KO with in vitro and in vivo functional validation, multiple orthogonal methods","pmids":["32098629"],"is_preprint":false},{"year":2011,"finding":"MUC5AC expressed on the surface of pancreatic cancer cells enables escape from host immunosurveillance; MUC5AC knockdown (siRNA) suppresses in vivo tumor growth and allows neutrophil (Gr-1+) and B-cell (CD45R/B220+) infiltration. Tumor growth of MUC5AC-knockdown cells is restored upon neutrophil depletion, indicating MUC5AC specifically suppresses neutrophil anti-tumor activity.","method":"Stable siRNA knockdown in SW1990 and BxPC3 cells, xenograft studies, neutrophil depletion with anti-Gr-1 mAb, immunohistochemistry, serum antibody detection","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown + in vivo neutrophil depletion rescue experiment establishing mechanism, single lab","pmids":["21249315"],"is_preprint":false},{"year":2013,"finding":"MUC5AC protects pancreatic cancer cells from TRAIL-induced apoptosis: MUC5AC-knockdown cells showed significantly increased active caspase-3 after TRAIL addition, while control cells did not, indicating MUC5AC inhibits TRAIL-mediated death pathways.","method":"Stable siRNA knockdown in SW1990 cells, TRAIL treatment, active caspase-3 measurement, immunocyte-depleted animal models","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown + caspase activation assay, mechanistic rescue by neutrophil depletion, single lab","pmids":["23292004"],"is_preprint":false},{"year":2021,"finding":"ST6GalNAc-I catalyzes sialylation (STn modification) of MUC5AC; immunoprecipitation of MUC5AC in p53R175H-expressing cells showed higher affinity toward STn. ST6GalNAc-I knockout reduces MUC5AC glycosylation (less STn), decreases cell migration, and reduces liver metastasis in vivo.","method":"Immunoprecipitation of MUC5AC for STn, ST6GalNAc-I CRISPR knockout, in vivo metastasis models, ectopic p53 mutant expression","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating MUC5AC-STn association + CRISPR KO with in vivo validation, single lab","pmids":["33792183"],"is_preprint":false},{"year":2022,"finding":"MUC5B and MUC5AC play distinct roles in mucociliary transport: MUC5B deficiency impairs mucus transport (reduced overall transport), while MUC5AC deficiency results in discoordinated mucociliary transport, demonstrating that MUC5AC spatially aligns mucociliary transport on human airway epithelium.","method":"CRISPR-based generation of MUC5B- and MUC5AC-deficient human airway epithelial tissue cultures, mucociliary transport measurement","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean CRISPR KO of each mucin separately with quantitative transport phenotype in human ALI cultures, functional distinction between the two mucins","pmids":["36427316"],"is_preprint":false},{"year":2020,"finding":"Muc5ac expression protects the colonic barrier during experimental colitis by limiting bacterial epithelial contact and translocation to mesenteric lymph nodes; Muc5ac-/- mice have worsened DSS colitis, and antibiotic treatment normalizes colitis severity in Muc5ac-/- mice, confirming that the protective effect is mediated by bacterial exclusion.","method":"Muc5ac-/- mouse model, DSS colitis, bacterial-epithelial contact quantification, bacterial translocation assay, 16S rRNA sequencing, antibiotic treatment","journal":"Inflammatory bowel diseases","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with mechanistic rescue by antibiotics, bacterial translocation assay establishing mechanism in vivo","pmids":["32385500"],"is_preprint":false},{"year":2018,"finding":"Muc5ac is required for KRAS-driven lung adenocarcinoma development: mice lacking Muc5ac have significantly reduced tumor development in both chemically-induced (urethane) and transgenic mutant-Kras lung adenocarcinoma models.","method":"Muc5ac-/- mice crossed with urethane-induced and transgenic Kras-mutant lung adenocarcinoma models, tumor burden quantification","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in two independent in vivo tumor models, single lab, functional role established without detailed molecular mechanism","pmids":["30089720"],"is_preprint":false},{"year":2020,"finding":"EGFR activation reduces claudin1 expression, and claudin1 knockdown induces MUC5AC overexpression in vitro and in vivo; restoring claudin1 expression by EGFR antagonism (erlotinib) reduces MUC5AC expression, placing claudin1 as a negative regulator of MUC5AC downstream of EGFR.","method":"claudin1 siRNA knockdown in 16HBE cells and HDM mouse model, erlotinib treatment, in vitro and in vivo MUC5AC measurement","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown + pharmacologic rescue in vitro and in vivo, single lab","pmids":["32132671"],"is_preprint":false},{"year":2020,"finding":"MUC1-dependent EGFR activation mediates cigarette smoke-induced goblet cell metaplasia and Muc5ac overproduction; Muc1-knockout rats show no EGFR phosphorylation and are protected from GCM and Muc5ac overproduction after cigarette smoke exposure. MUC1 translocates from the apical surface to intracellular compartments in response to cigarette smoke.","method":"Muc1-knockout rat model, cigarette smoke exposure, EGFR phosphorylation Western blot, MUC1 localization immunostaining, siRNA knockdown in human lung cells and primary rat airway epithelial cells","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in vivo + siRNA in vitro + localization data, single lab","pmids":["32401676"],"is_preprint":false},{"year":2019,"finding":"In neutrophil elastase (HNE)-induced MUC5AC overexpression in chronic rhinosinusitis, autophagy increases MUC5AC secretion by promoting JNK/c-Jun phosphorylation; siRNA knockdown of Beclin-1, Atg5, or c-Jun each block HNE-induced MUC5AC secretion in primary human nasal epithelial cells.","method":"Bafilomycin A1 (autophagy inhibitor), BECN1-siRNA, Atg5-siRNA, c-Jun-siRNA, SP600125 (JNK inhibitor), TEM for autophagosomes, in CRS patient mucosa and primary HNECs","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple siRNA targets converging on autophagy-JNK-c-Jun pathway in primary cells, single lab","pmids":["30909132"],"is_preprint":false},{"year":2018,"finding":"IL-13 induces MUC5AC expression in nasal epithelial cells through ERK1/2 activation and C-JUN upregulation mediated by IL-13Ralpha2, and this can be attenuated by ERK1/2 inhibitor or dexamethasone.","method":"ERK1/2 inhibitor, siRNA, MUC5AC mRNA/protein quantification, ERK phosphorylation Western blot in primary hNECs and ALI cultures","journal":"Allergy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlation between IL-13Ralpha2 and MUC5AC plus pharmacologic ERK inhibition, no receptor-specific genetic knockout","pmids":["29405354"],"is_preprint":false},{"year":2014,"finding":"IL-13 induces MUC5AC expression in mouse tracheal epithelial cells via a PI3K-NFAT3 pathway: IL-13 promotes NFAT3 dephosphorylation/activation, and both PI3K inhibitor (LY294002) and NFAT inhibitor (Cyclosporin A) block IL-13-induced MUC5AC production without affecting Foxa2 or mClca3 expression.","method":"PI3K inhibitor LY294002, NFAT inhibitor Cyclosporin A, phosphorylation assay for NFAT3, MUC5AC mRNA and protein measurement in ALI cultures of mouse tracheal epithelial cells","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacologic inhibitors only, no genetic knockdown of NFAT3, single lab","pmids":["24583134"],"is_preprint":false},{"year":2013,"finding":"PGE2 induces MUC5AC expression in human intrahepatic biliary epithelial cells via EP4 receptor-p38 MAPK signaling; EP4 agonist increases and EP4 antagonist decreases MUC5AC expression, and p38 MAPK inhibitor reduces PGE2-induced MUC5AC expression.","method":"EP4 agonist/antagonist, p38 MAPK inhibitor, LPS stimulation with TLR4 antagonist and NF-kappaB inhibitor in HIBECs; bile samples from hepatolithiasis patients","journal":"Annals of hepatology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacologic receptor/pathway inhibition only, no genetic knockdown, single lab","pmids":["23619266"],"is_preprint":false},{"year":2022,"finding":"ITGB4 deficiency in airway epithelial cells induces MUC5AC overexpression through the EGFR/ERK/c-Jun pathway; EGFR inhibitors prevent mucus hypersecretion and MUC5AC overexpression in ITGB4-deficient mice after RSV infection.","method":"ITGB4 siRNA knockdown in HBE cells, ITGB4-deficient mice, RSV infection, EGFR inhibitor treatment, ERK/c-Jun pathway Western blot","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA in vitro + genetic KO mouse in vivo + EGFR inhibitor rescue, single lab","pmids":["34975337"],"is_preprint":false},{"year":2016,"finding":"Spleen tyrosine kinase (SYK) induces MUC5AC expression in human airway epithelial cells via ERK2 and p38 MAPK signaling pathways; ERK2 siRNA and p38 MAPK siRNA each block SYK-induced MUC5AC expression.","method":"ERK1/2 inhibitor U0126, p38 inhibitor SB203580, ERK2 siRNA, p38 MAPK siRNA, SYK stimulation in NCI-H292 and primary human nasal epithelial cells","journal":"American journal of rhinology & allergy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — siRNA knockdown of downstream effectors only, no direct SYK knockout, single lab","pmids":["26980390"],"is_preprint":false},{"year":2023,"finding":"Oxidative stress induces MUC5AC expression in airway epithelial cells via a mitochondrial damage-dependent STING (stimulator of interferon genes) pathway; STING knockout suppresses H2O2-induced MUC5AC expression, while cGAS knockout does not.","method":"STING and cGAS CRISPR knockout cells, hydrogen peroxide treatment, mitochondrial antioxidants, cytosolic mitochondrial DNA measurement in NCI-H292 and primary NHBECs","journal":"FASEB bioAdvances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO of STING vs cGAS distinguishing cGAS-independent STING mechanism, two cell types, single lab","pmids":["37020748"],"is_preprint":false},{"year":2024,"finding":"MUC5AC interacts with Annexin A2 (ANXA2) in lung adenocarcinoma cells (identified by immunoprecipitation and proteomic analysis); this MUC5AC/ANXA2 signaling axis activates downstream matrix metalloproteases and facilitates ECM degradation to promote brain metastasis. A peptide inhibitor disrupting MUC5AC-ANXA2 interaction abrogates metastasis.","method":"Immunoprecipitation, proteomic analysis, MUC5AC depletion in brain-tropic cell lines, intracardiac injection brain metastasis models, peptide inhibitor","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + proteomics identifying MUC5AC-ANXA2 interaction + in vivo rescue with peptide inhibitor, single lab","pmids":["38825648"],"is_preprint":false},{"year":2022,"finding":"NOTCH3 intracellular domain (NICD3) regulates MUC5AC (and MUC2) expression by directly recruiting SMARCA4 (BRG1/transcription activator); NOTCH3 controls MUC5AC transcription in a SMARCA4-dependent manner in colorectal cancer cells.","method":"Co-immunoprecipitation of NICD3 and SMARCA4, RNA sequencing for target gene identification, functional assays in CRC cells","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying protein-protein interaction + RNA-seq + functional validation, single lab","pmids":["35900231"],"is_preprint":false},{"year":2024,"finding":"MUC5AC contains polymorphic variable number tandem repeats (VNTRs) with cysteine-rich domain and VNTR copy-number variation defining 30 allelic variants encoding 16 distinct proteins (5,249-6,325 aa). Long-read sequencing and haplotype analysis reveal three phylogenetic clades (H1, H2, H3) with signatures of positive selection in East Asians and balancing selection in Europeans.","method":"Long-read sequencing and assembly of 206 human and 20 NHP haplotypes, Locityper genotyping of 2,600 samples from 1000 Genomes Project, Tajima's D and linkage disequilibrium analysis","journal":"American journal of human genetics","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — structural/genetic characterization without functional validation of specific variants","pmids":["38991590"],"is_preprint":false},{"year":2001,"finding":"MUC5AC gene organization was fully elucidated: the 5' region encodes a signal peptide, four pro-von Willebrand factor-like D domains (D1, D2, D', D3), and the central region contains 9 cysteine-rich domains interspersed with serine/threonine/proline-rich domains and four tandem repeat arrays (TR1-TR4). Length polymorphism is due to variable numbers of tandem repeats in TR1 and TR4.","method":"Full-length cDNA sequencing, Southern blot analysis for allelic variations","journal":"The Biochemical journal","confidence":"Low","confidence_rationale":"Tier 4 / Strong — sequence/structural characterization, no functional experiments; replicated conceptually by subsequent structural studies","pmids":["11535137"],"is_preprint":false}],"current_model":"MUC5AC is a gel-forming secreted mucin whose expression is regulated by multiple converging signaling pathways in airway and other epithelial cells—including NF-kappaB, EGFR/TACE/TGF-alpha, STAT6, ERK/MAPK, Notch, DUOX1-ROS, and autophagy/JNK/c-Jun cascades downstream of stimuli such as IL-1beta, IL-13, IL-17A, neutrophil elastase, and cigarette smoke—whose biosynthesis requires C-mannosylation of Cys subdomains in the ER for proper folding and secretion, whose mucosal function includes spatially aligning mucociliary transport and providing a barrier against luminal bacteria, and which in cancer contexts interacts physically with CD44 (activating Src), ANXA2 (activating MMPs for metastasis), and undergoes ST6GalNAc-I-mediated sialylation to promote tumor progression and immune evasion."},"narrative":{"mechanistic_narrative":"MUC5AC is a large gel-forming secreted mucin built from pro-von Willebrand factor-like D domains, cysteine-rich subdomains, and serine/threonine/proline-rich tandem-repeat arrays whose copy-number polymorphism underlies extensive allelic variation [PMID:11535137]. Its biosynthesis requires C-mannosylation at WXXW motifs within the Cys1 and Cys5 subdomains in the endoplasmic reticulum, a modification needed for proper folding and ER export [PMID:14718370]. At mucosal surfaces MUC5AC performs distinct protective functions: it spatially coordinates mucociliary transport on airway epithelium, such that its loss produces discoordinated rather than reduced transport [PMID:36427316], and in the gut it limits bacterial contact with and translocation across the colonic epithelium, protecting against experimental colitis [PMID:32385500]. MUC5AC transcription is a convergence point for many epithelial signaling cascades, dominated by EGFR activation triggered by TACE-mediated cleavage of pro-TGF-alpha downstream of DUOX1-generated ROS, microbial serine proteases, and muscarinic M3 receptor signaling [PMID:15640347, PMID:21685325, PMID:20525722], by NF-kappaB acting both directly and through HIF-1alpha [PMID:19841186, PMID:29031476], and by STAT6, Notch, and MAPK-dependent inputs from type 2 and IL-17 cytokines [PMID:21622856, PMID:27588910, PMID:24892823]. In cancer, MUC5AC acts beyond a secreted barrier: it physically engages CD44 to activate Src and drives colorectal tumor invasion and chemoresistance [PMID:32098629], binds ANXA2 to activate matrix metalloproteases and promote brain metastasis [PMID:38825648], undergoes ST6GalNAc-I-mediated STn sialylation that supports migration and metastasis [PMID:33792183], and is required for KRAS-driven lung adenocarcinoma and for suppression of anti-tumor neutrophil immunity in pancreatic cancer [PMID:21249315, PMID:30089720].","teleology":[{"year":2001,"claim":"Establishing the domain architecture of MUC5AC defined it as a von Willebrand factor-type gel-forming mucin and explained the molecular basis of its length polymorphism.","evidence":"Full-length cDNA sequencing and Southern blot of allelic variants","pmids":["11535137"],"confidence":"Low","gaps":["No functional consequences assigned to individual domains","Tandem-repeat polymorphism not linked to phenotype"]},{"year":2004,"claim":"Identifying C-mannosylation of the Cys subdomains answered how MUC5AC achieves proper folding and ER export, linking a specific co-translational glycosylation to secretion competence.","evidence":"WXXW mutagenesis, pulse-chase, lectin binding, and C-mannosylation-defective CHO-Lec35.1 cells with GFP-tagged subdomains","pmids":["14718370"],"confidence":"High","gaps":["Done on isolated Cys subdomains, not full-length mucin","Enzyme responsible for C-mannosylation not identified"]},{"year":2005,"claim":"The DUOX1/ROS → TACE → pro-TGF-alpha → EGFR cascade established a unifying oxidant-driven route by which airway stimuli converge on MUC5AC transcription.","evidence":"siRNA, ROS scavengers, NADPH oxidase and TACE inhibitors with PMA/neutrophil elastase in HBE and NCI-H292 cells","pmids":["15640347"],"confidence":"High","gaps":["Transcription factors terminal to EGFR not defined here","Single airway context"]},{"year":2007,"claim":"Reporter and in vivo work showed SMAD4 and HIF-1alpha bind conserved Muc5ac promoter motifs required for activity, and that Muc5ac is the dominant induced mucin in allergic airways.","evidence":"OVA mouse model plus luciferase promoter mutagenesis in a Clara cell line","pmids":["17463395"],"confidence":"High","gaps":["Upstream activators of SMAD4/HIF-1alpha at the promoter not resolved"]},{"year":2009,"claim":"ChIP and reporter assays mapped a specific NF-kappaB (p50) site in the MUC5AC promoter, establishing direct cytokine-driven transcriptional control by IL-1beta and IL-17A.","evidence":"Reporter assays, p65 siRNA, NF-kappaB inhibitor, and ChIP in primary NHBE and HBE1 cells","pmids":["19841186"],"confidence":"High","gaps":["Cooperation with other promoter factors not addressed"]},{"year":2011,"claim":"Microbial serine proteases and EGFR-Notch crosstalk were shown to feed the EGFR axis, broadening the range of stimuli that activate MUC5AC via TACE and amplifying signaling through reciprocal Notch-EGFR loops.","evidence":"Protease and TACE inhibitors, siRNA, neutralizing antibodies (Aspergillus); gamma-secretase inhibitors, Notch1 siRNA, NICD overexpression (Notch) in NCI-H292 and primary HBE cells","pmids":["21685325","21622856"],"confidence":"Medium","gaps":["Single-lab pathway dissections","Quantitative contribution relative to other inputs unclear"]},{"year":2016,"claim":"Defining the STAT6 → TMEM16A → ERK route and Lyn-mediated negative regulation of STAT6 clarified how type 2 cytokine signaling is tuned at the MUC5AC promoter.","evidence":"STAT6 inhibition and TMEM16A siRNA (IL-13); Lyn gain/loss-of-function with ChIP for STAT6 binding in 16HBE and OVA mice","pmids":["27588910","28205598"],"confidence":"Medium","gaps":["Single cell lines/labs","Integration with NF-kappaB inputs not tested"]},{"year":2020,"claim":"Co-IP and CRISPR knockout established MUC5AC as an active cancer-promoting protein through physical CD44 engagement and Src activation, beyond its role as a secreted barrier.","evidence":"Reciprocal co-IP, CRISPR/Cas9 knockout, in vitro and orthotopic in vivo assays in colorectal cancer cells","pmids":["32098629"],"confidence":"High","gaps":["Binding interface not mapped","Generalizability beyond CRC unestablished"]},{"year":2020,"claim":"Genetic knockout in the colon demonstrated that MUC5AC's barrier function operates by excluding bacteria, with antibiotics rescuing the colitis phenotype.","evidence":"Muc5ac-/- mice, DSS colitis, bacterial translocation assays, 16S sequencing, antibiotic rescue","pmids":["32385500"],"confidence":"High","gaps":["Mechanism of bacterial exclusion at molecular level not defined"]},{"year":2022,"claim":"Separate CRISPR knockout of MUC5AC and MUC5B in human airway cultures showed MUC5AC uniquely coordinates the spatial alignment of mucociliary transport rather than its overall magnitude.","evidence":"CRISPR-deficient human airway ALI cultures with quantitative transport measurement","pmids":["36427316"],"confidence":"High","gaps":["Biophysical basis of coordination not resolved"]},{"year":2024,"claim":"Identification of the MUC5AC-ANXA2 axis and ST6GalNAc-I-mediated STn sialylation extended MUC5AC's tumor-promoting mechanism to MMP activation/metastasis and glycan-driven progression.","evidence":"Co-IP/proteomics and peptide inhibitor in brain-metastasis models (ANXA2); MUC5AC STn immunoprecipitation and ST6GalNAc-I CRISPR knockout in metastasis models (sialylation)","pmids":["38825648","33792183"],"confidence":"Medium","gaps":["Single-lab studies","Interaction interfaces and glycosite specificity incompletely defined"]},{"year":null,"claim":"How the many converging transcriptional inputs are integrated at the native MUC5AC locus, and whether VNTR allelic variants confer functionally distinct mucin properties, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No combinatorial promoter logic established across the cited pathways","Functional consequences of the 16 allelic protein variants untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[24,25,39]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[20]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[24,25]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[21]}],"pathway":[],"complexes":[],"partners":["CD44","ANXA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P98088","full_name":"Mucin-5AC","aliases":["Gastric mucin","Major airway glycoprotein","Mucin-5 subtype AC, tracheobronchial","Tracheobronchial mucin","TBM"],"length_aa":5654,"mass_kda":585.6,"function":"Gel-forming glycoprotein of gastric and respiratory tract epithelia that protects the mucosa from infection and chemical damage by binding to inhaled microorganisms and particles that are subsequently removed by the mucociliary system (PubMed:14535999, PubMed:14718370). Interacts with H.pylori in the gastric epithelium, Barrett's esophagus as well as in gastric metaplasia of the duodenum (GMD) (PubMed:14535999)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P98088/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MUC5AC","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":74,"dependency_fraction":0.013513513513513514},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MUC5AC","total_profiled":1310},"omim":[{"mim_id":"615131","title":"UDP-N-ACETYL-ALPHA-D-GALACTOSAMINE:POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE 15; GALNT15","url":"https://www.omim.org/entry/615131"},{"mim_id":"610290","title":"UDP-N-ACETYL-ALPHA-D-GALACTOSAMINE:POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE 12; GALNT12","url":"https://www.omim.org/entry/610290"},{"mim_id":"608225","title":"UDP-N-ACETYL-ALPHA-D-GALACTOSAMINE:POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE 14; GALNT14","url":"https://www.omim.org/entry/608225"},{"mim_id":"607412","title":"BPI FOLD-CONTAINING PROTEIN, FAMILY A, MEMBER 1; BPIFA1","url":"https://www.omim.org/entry/607412"},{"mim_id":"606963","title":"PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; COPD","url":"https://www.omim.org/entry/606963"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"stomach 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pathway on PM2.5-induced Muc5ac in Beas-2B cells.","date":"2020","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/32678753","citation_count":15,"is_preprint":false},{"pmid":"27296651","id":"PMC_27296651","title":"Increased expression of hCLCA1 in chronic rhinosinusitis and its contribution to produce MUC5AC.","date":"2016","source":"The Laryngoscope","url":"https://pubmed.ncbi.nlm.nih.gov/27296651","citation_count":14,"is_preprint":false},{"pmid":"34975337","id":"PMC_34975337","title":"ITGB4 deficiency induces mucus hypersecretion by upregulating MUC5AC in RSV-infected airway epithelial cells.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34975337","citation_count":14,"is_preprint":false},{"pmid":"15568157","id":"PMC_15568157","title":"MUC1, MUC2 and MUC5AC expressions in cardiac myxoma.","date":"2004","source":"Virchows Archiv : an international journal of 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allergy","url":"https://pubmed.ncbi.nlm.nih.gov/26980390","citation_count":10,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":57476,"output_tokens":10224,"usd":0.162894,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20593,"output_tokens":3585,"usd":0.096295,"stage2_stop_reason":"end_turn"},"total_usd":0.259189,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"Dual oxidase 1 (Duox1) generates reactive oxygen species that activate TACE (TNF-alpha-converting enzyme), leading to cleavage of pro-TGF-alpha and subsequent EGFR activation, resulting in MUC5AC expression in airway epithelial cells. PKCdelta/PKC lies upstream of Duox1 in this cascade.\",\n      \"method\": \"siRNA knockdown of Duox1, ROS scavengers, NADPH oxidase inhibitors, TACE inhibition; stimulation with PMA and neutrophil elastase in human bronchial epithelial cells and NCI-H292 cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, pharmacologic inhibitors, ROS measurement) in two cell models, pathway validated at multiple nodes\",\n      \"pmids\": [\"15640347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-1beta and IL-17A induce MUC5AC expression via NF-kappaB-dependent transcriptional activation. A critical NF-kappaB binding site at position -3594/-3582 in the MUC5AC promoter was identified, and chromatin immunoprecipitation confirmed enhanced binding of NF-kappaB subunit p50 to this region following cytokine stimulation.\",\n      \"method\": \"Reporter gene assay, siRNA knockdown of p65, NF-kappaB small molecule inhibitor, ChIP analysis in well-differentiated primary normal human bronchial epithelial cells and HBE1 cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — promoter reporter assay + ChIP + siRNA knockdown, multiple orthogonal methods in two cell models\",\n      \"pmids\": [\"19841186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In allergic mouse airways, Muc5ac is the predominant gel-forming mucin induced, localizing to bronchial Clara cells. SMAD4 and HIF-1alpha bind to evolutionarily conserved motifs in the Muc5ac promoter and are required for promoter function; mutation of their recognition motifs abolishes promoter activity.\",\n      \"method\": \"Murine OVA model, luciferase reporter gene assay with promoter mutations, transcription factor binding analysis in transformed Clara cell line\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reporter assay with mutagenesis + in vivo model, multiple methods establishing both in vivo relevance and molecular mechanism\",\n      \"pmids\": [\"17463395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The Cys subdomains of MUC5AC (Cys1 and Cys5) undergo C-mannosylation at their WXXW motifs in the endoplasmic reticulum. Mutation of the first tryptophan in the WXXW motif or expression in C-mannosylation-defective CHO-Lec35.1 cells reduces secretion and causes ER retention, indicating C-mannosylation is required for proper folding and/or ER export of MUC5AC.\",\n      \"method\": \"Pulse-chase labeling, mutagenesis of WXXW motif, lectin binding assays, live cell imaging of GFP-tagged Cys subdomains, C-mannosylation-defective cell line (CHO-Lec35.1)\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including mutagenesis, defective cell line, pulse-chase, and live imaging, all converging on the same mechanistic conclusion\",\n      \"pmids\": [\"14718370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IL-1beta induces MUC5AC expression in NCI-H292 airway epithelial cells through a COX-2/PGE2 pathway, with ERK1/2 and p38 MAPK acting upstream of COX-2 induction.\",\n      \"method\": \"Selective COX-2 inhibitor (NS398), MAPK inhibitors (PD98059, SB203580), exogenous PGE2 addition; mRNA and protein quantification\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic pathway dissection with multiple inhibitors in single cell line, no genetic knockdown validation\",\n      \"pmids\": [\"12391274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Neutrophil elastase induces MUC5AC gene expression through an oxidant-dependent mechanism involving reactive oxygen species (hydroxyl radical/peroxynitrite) in airway epithelial cells.\",\n      \"method\": \"ROS scavenger DMTU, intracellular redox indicator dichlorodihydrofluorescein in A549 and primary normal human bronchial epithelial cells\",\n      \"journal\": \"Chest\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic inhibition confirmed in two cell types, single lab\",\n      \"pmids\": [\"10843967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NQO1 (NAD(P)H:quinone oxidoreductase 1) mediates neutrophil elastase-induced oxidant stress and MUC5AC mRNA expression in airway epithelial cells; siRNA knockdown of NQO1 abrogates MUC5AC expression and reduces NE-induced lipid peroxidation.\",\n      \"method\": \"Pharmacologic NQO1 inhibitor (dicumarol), siRNA knockdown of NQO1, lipid peroxidation assay in A549 cells and primary normal human bronchial epithelial cells\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both pharmacologic inhibition and siRNA knockdown in two cell types, single lab\",\n      \"pmids\": [\"17395013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Aspergillus fumigatus serine protease activity activates TACE, which cleaves membrane-bound pro-TGF-alpha; this leads to EGFR activation and induction of MUC5AC expression in airway epithelial cells. Cysteine protease inhibition had no effect, only serine protease inhibition blocked TACE activation and MUC5AC induction.\",\n      \"method\": \"Serine/cysteine protease inhibitors, TACE inhibitors, TACE siRNA, EGFR/TGF-alpha neutralizing antibodies in NCI-H292 cells and primary airway epithelial cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (protease inhibitors, siRNA, neutralizing antibodies) in two cell types establishing sequential pathway\",\n      \"pmids\": [\"21685325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Neuregulin 1beta1 (NRG1beta1) induces MUC5AC and MUC5B expression in primary human bronchial epithelial cells via ErbB2 and ErbB3 receptors (not ErbB4), with downstream involvement of p38 MAPK, ERK1/2, and PI3K, and induction of ErbB2, AKT, and ERK1/2 phosphorylation.\",\n      \"method\": \"ErbB receptor-specific inhibitors, kinase inhibitors (p38, ERK1/2, PI3K), Western blot for phosphorylation, time- and dose-response studies in primary HBECs and in vivo antigen-challenged mice\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic pathway dissection with multiple inhibitors, receptor specificity tested, validated in vivo, single lab\",\n      \"pmids\": [\"19556605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PGF2alpha induces MUC5AC overproduction in human tracheobronchial epithelial cells via a sequential signaling cascade: PKC → ERK → p90RSK → CREB. CREB directly interacts with the MUC5AC promoter via a cAMP response element, and suppression of each signaling molecule along this pathway abrogates MUC5AC expression.\",\n      \"method\": \"Pathway inhibitors, promoter reporter assay (CRE-dependent MUC5AC promoter activity), CREB-MUC5AC promoter interaction assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter + pathway inhibitor cascade, single lab\",\n      \"pmids\": [\"19201889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Muscarinic M3 receptor (not M2) mediates carbachol-induced MUC5AC expression in human airway epithelial cells via EGFR transactivation and p44/42 MAPK phosphorylation; aclidinium inhibits carbachol- and cigarette smoke-induced MUC5AC overexpression through this pathway.\",\n      \"method\": \"siRNA against muscarinic receptor subtypes (M2, M3), EGFR tyrosine kinase inhibitor AG1478, phospho-EGFR and phospho-MAPK Western blot, in human bronchial tissue and cultured epithelial cells\",\n      \"journal\": \"The European respiratory journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor subtype identified by siRNA knockdown + pharmacologic inhibition in two tissue/cell settings, single lab\",\n      \"pmids\": [\"20525722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"EGF-induced MUC5AC expression requires bidirectional signaling between EGFR and Notch pathways: EGFR induces Notch intracellular domain (NICD) generation in an RBP-Jkappa-dependent manner, and Notch signaling amplifies EGFR/ERK activation. Forced NICD expression alone is sufficient to induce MUC5AC via EGFR-ERK activation.\",\n      \"method\": \"gamma-secretase inhibitors, Notch1 siRNA, NICD overexpression, EGFR antagonist antibody, EGFR and ERK inhibitors in NCI-H292 cells and primary human bronchial epithelial cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (siRNA, overexpression) and pharmacologic approaches in two cell types, single lab\",\n      \"pmids\": [\"21622856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Neutrophil elastase induces MUC5AC secretion via PAR2 (protease-activated receptor 2), which increases cytosolic calcium from ER stores and via store-operated calcium entry (SOCE) channels, subsequently activating PKC to stimulate secretion.\",\n      \"method\": \"PAR1/2/3 expression analysis, PAR2 expression measurement after NE, calcium measurement with thapsigargin (ER depletion) and 2-APB (SOCE inhibitor), PKC activation assay in Calu-3 cells\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic dissection of calcium pathway with multiple inhibitors, single cell line, single lab\",\n      \"pmids\": [\"23392769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-13 induces MUC5AC expression in human airway epithelial cells via STAT6-dependent upregulation of TMEM16A, whose chloride channel activity activates ERK1/2; TMEM16A knockdown or channel inhibition reduces ERK1/2 phosphorylation and MUC5AC expression.\",\n      \"method\": \"STAT6 inhibition, TMEM16A siRNA knockdown, chloride channel inhibitor T16Ainh-A01, ERK1/2 inhibitor PD98059, mRNA and protein quantification in HBE16 cells\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA + pharmacologic inhibition at multiple pathway nodes, single cell line, single lab\",\n      \"pmids\": [\"27588910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-17A induces MUC5AC expression and goblet cell hyperplasia through the Act1-mediated signaling pathway involving MAPK (ERK, p38, JNK) activation; siRNA knockdown of IL-17RA, IL-17RC, and Act1 each block IL-17A-induced MUC5AC production.\",\n      \"method\": \"siRNA knockdown of IL-17RA, IL-17RC, Act1; MAPK Western blot; qPCR and Western blot in polyp epithelial cells and NCI-H292 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple siRNA targets validating sequential pathway, two cell systems, single lab\",\n      \"pmids\": [\"24892823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-1beta upregulates Muc5ac expression via NF-kappaB-induced HIF-1alpha: NF-kappaB activation induces HIF-1alpha, which directly binds the Muc5ac promoter and enhances its transcriptional activity. HIF-1alpha siRNA knockdown and NF-kappaB inhibition (Bay11-7082) each reduce IL-1beta-induced Muc5ac expression.\",\n      \"method\": \"siRNA knockdown of HIF-1alpha, NF-kappaB inhibitor, luciferase reporter assay with Muc5ac promoter, EMSA for HIF-1alpha binding to Muc5ac promoter in NHBECs\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter + EMSA + siRNA knockdown in primary cells, single lab\",\n      \"pmids\": [\"29031476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lyn kinase negatively regulates MUC5AC expression by downregulating STAT6 and its binding to the Muc5ac promoter; Lyn overexpression decreases IL-4/IL-13-induced MUC5AC expression and STAT6 phosphorylation, while Lyn knockdown increases them. ChIP confirmed that Lyn overexpression decreases STAT6 binding to the Muc5ac promoter.\",\n      \"method\": \"Lyn overexpression and siRNA knockdown in 16HBE cells and OVA mouse model, ChIP analysis for STAT6 binding to Muc5ac promoter, STAT6 phosphorylation Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP + gain/loss of function in vitro and in vivo, single lab\",\n      \"pmids\": [\"28205598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Benzo(a)pyrene induces MUC5AC expression through an AhR/mitochondrial ROS/ERK pathway: AhR nuclear translocation activates CYP1s (CYP1A1/CYP1B1), increasing mitochondrial ROS, which activates ERK and CREB to drive MUC5AC promoter activity. AhR overexpression enhances and AhR/CREB siRNA knockdown reduces BaP-induced MUC5AC.\",\n      \"method\": \"AhR siRNA and overexpression lentivirus, CREB siRNA, CYP1 inhibitor, mitochondrial ROS inhibitor Mito-TEMP, ERK inhibitor U0126, luciferase MUC5AC promoter assay in NCI-H292 cells\",\n      \"journal\": \"Ecotoxicology and environmental safety\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple siRNA targets + pharmacologic inhibitors + promoter reporter, single cell line, single lab\",\n      \"pmids\": [\"33421718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"dsRNA (poly(I:C)) synergistically amplifies TGF-alpha-induced MUC5AC expression via sustained ERK activation; this occurs through poly(I:C)-mediated inhibition of MKP3 (MAPK phosphatase 3) upregulation. Overexpression of MKP3 completely suppresses the poly(I:C)-enhanced MUC5AC induction.\",\n      \"method\": \"MEK1/2 inhibitor U0126, MKP3 overexpression, ERK phosphorylation Western blot, MUC5AC promoter activity assay in NCI-H292 cells and primary HBECs\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MKP3 overexpression rescue experiment + pharmacologic inhibition in two cell types, single lab\",\n      \"pmids\": [\"19109160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TGF-beta3 induces MUC5AC hyper-expression in airway epithelium through autophagy activation and subsequent AP-1 (activator protein-1) activation; Smad2/3 pathway mediates TGF-beta3-induced autophagy. Inhibition of autophagy reduces TGF-beta3-induced MUC5AC expression in vitro and in vivo.\",\n      \"method\": \"Autophagy inhibitors in OVA mouse model, autophagy induction by TGF-beta3 in human bronchial epithelial cells, AP-1 activation measurement, Smad2/3 pathway analysis\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — autophagy inhibition in vivo and in vitro with pathway analysis, single lab\",\n      \"pmids\": [\"29997053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MUC5AC physically interacts with CD44 (co-immunoprecipitation), and this interaction activates Src signaling. MUC5AC knockout (CRISPR/Cas9) reduces colorectal cancer invasion/migration, increases apoptosis, and sensitizes cells to 5-FU and oxaliplatin via modulation of p53/p21/beta-catenin/CD44/Lgr5 signaling.\",\n      \"method\": \"CRISPR/Cas9 knockout, siRNA knockdown, co-immunoprecipitation, in vitro functional assays, in vivo orthotopic mouse models in CRC cell lines\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing MUC5AC-CD44 interaction + CRISPR KO with in vitro and in vivo functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"32098629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MUC5AC expressed on the surface of pancreatic cancer cells enables escape from host immunosurveillance; MUC5AC knockdown (siRNA) suppresses in vivo tumor growth and allows neutrophil (Gr-1+) and B-cell (CD45R/B220+) infiltration. Tumor growth of MUC5AC-knockdown cells is restored upon neutrophil depletion, indicating MUC5AC specifically suppresses neutrophil anti-tumor activity.\",\n      \"method\": \"Stable siRNA knockdown in SW1990 and BxPC3 cells, xenograft studies, neutrophil depletion with anti-Gr-1 mAb, immunohistochemistry, serum antibody detection\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown + in vivo neutrophil depletion rescue experiment establishing mechanism, single lab\",\n      \"pmids\": [\"21249315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MUC5AC protects pancreatic cancer cells from TRAIL-induced apoptosis: MUC5AC-knockdown cells showed significantly increased active caspase-3 after TRAIL addition, while control cells did not, indicating MUC5AC inhibits TRAIL-mediated death pathways.\",\n      \"method\": \"Stable siRNA knockdown in SW1990 cells, TRAIL treatment, active caspase-3 measurement, immunocyte-depleted animal models\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown + caspase activation assay, mechanistic rescue by neutrophil depletion, single lab\",\n      \"pmids\": [\"23292004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ST6GalNAc-I catalyzes sialylation (STn modification) of MUC5AC; immunoprecipitation of MUC5AC in p53R175H-expressing cells showed higher affinity toward STn. ST6GalNAc-I knockout reduces MUC5AC glycosylation (less STn), decreases cell migration, and reduces liver metastasis in vivo.\",\n      \"method\": \"Immunoprecipitation of MUC5AC for STn, ST6GalNAc-I CRISPR knockout, in vivo metastasis models, ectopic p53 mutant expression\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating MUC5AC-STn association + CRISPR KO with in vivo validation, single lab\",\n      \"pmids\": [\"33792183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MUC5B and MUC5AC play distinct roles in mucociliary transport: MUC5B deficiency impairs mucus transport (reduced overall transport), while MUC5AC deficiency results in discoordinated mucociliary transport, demonstrating that MUC5AC spatially aligns mucociliary transport on human airway epithelium.\",\n      \"method\": \"CRISPR-based generation of MUC5B- and MUC5AC-deficient human airway epithelial tissue cultures, mucociliary transport measurement\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean CRISPR KO of each mucin separately with quantitative transport phenotype in human ALI cultures, functional distinction between the two mucins\",\n      \"pmids\": [\"36427316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Muc5ac expression protects the colonic barrier during experimental colitis by limiting bacterial epithelial contact and translocation to mesenteric lymph nodes; Muc5ac-/- mice have worsened DSS colitis, and antibiotic treatment normalizes colitis severity in Muc5ac-/- mice, confirming that the protective effect is mediated by bacterial exclusion.\",\n      \"method\": \"Muc5ac-/- mouse model, DSS colitis, bacterial-epithelial contact quantification, bacterial translocation assay, 16S rRNA sequencing, antibiotic treatment\",\n      \"journal\": \"Inflammatory bowel diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with mechanistic rescue by antibiotics, bacterial translocation assay establishing mechanism in vivo\",\n      \"pmids\": [\"32385500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Muc5ac is required for KRAS-driven lung adenocarcinoma development: mice lacking Muc5ac have significantly reduced tumor development in both chemically-induced (urethane) and transgenic mutant-Kras lung adenocarcinoma models.\",\n      \"method\": \"Muc5ac-/- mice crossed with urethane-induced and transgenic Kras-mutant lung adenocarcinoma models, tumor burden quantification\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in two independent in vivo tumor models, single lab, functional role established without detailed molecular mechanism\",\n      \"pmids\": [\"30089720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EGFR activation reduces claudin1 expression, and claudin1 knockdown induces MUC5AC overexpression in vitro and in vivo; restoring claudin1 expression by EGFR antagonism (erlotinib) reduces MUC5AC expression, placing claudin1 as a negative regulator of MUC5AC downstream of EGFR.\",\n      \"method\": \"claudin1 siRNA knockdown in 16HBE cells and HDM mouse model, erlotinib treatment, in vitro and in vivo MUC5AC measurement\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown + pharmacologic rescue in vitro and in vivo, single lab\",\n      \"pmids\": [\"32132671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MUC1-dependent EGFR activation mediates cigarette smoke-induced goblet cell metaplasia and Muc5ac overproduction; Muc1-knockout rats show no EGFR phosphorylation and are protected from GCM and Muc5ac overproduction after cigarette smoke exposure. MUC1 translocates from the apical surface to intracellular compartments in response to cigarette smoke.\",\n      \"method\": \"Muc1-knockout rat model, cigarette smoke exposure, EGFR phosphorylation Western blot, MUC1 localization immunostaining, siRNA knockdown in human lung cells and primary rat airway epithelial cells\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in vivo + siRNA in vitro + localization data, single lab\",\n      \"pmids\": [\"32401676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In neutrophil elastase (HNE)-induced MUC5AC overexpression in chronic rhinosinusitis, autophagy increases MUC5AC secretion by promoting JNK/c-Jun phosphorylation; siRNA knockdown of Beclin-1, Atg5, or c-Jun each block HNE-induced MUC5AC secretion in primary human nasal epithelial cells.\",\n      \"method\": \"Bafilomycin A1 (autophagy inhibitor), BECN1-siRNA, Atg5-siRNA, c-Jun-siRNA, SP600125 (JNK inhibitor), TEM for autophagosomes, in CRS patient mucosa and primary HNECs\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple siRNA targets converging on autophagy-JNK-c-Jun pathway in primary cells, single lab\",\n      \"pmids\": [\"30909132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-13 induces MUC5AC expression in nasal epithelial cells through ERK1/2 activation and C-JUN upregulation mediated by IL-13Ralpha2, and this can be attenuated by ERK1/2 inhibitor or dexamethasone.\",\n      \"method\": \"ERK1/2 inhibitor, siRNA, MUC5AC mRNA/protein quantification, ERK phosphorylation Western blot in primary hNECs and ALI cultures\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlation between IL-13Ralpha2 and MUC5AC plus pharmacologic ERK inhibition, no receptor-specific genetic knockout\",\n      \"pmids\": [\"29405354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-13 induces MUC5AC expression in mouse tracheal epithelial cells via a PI3K-NFAT3 pathway: IL-13 promotes NFAT3 dephosphorylation/activation, and both PI3K inhibitor (LY294002) and NFAT inhibitor (Cyclosporin A) block IL-13-induced MUC5AC production without affecting Foxa2 or mClca3 expression.\",\n      \"method\": \"PI3K inhibitor LY294002, NFAT inhibitor Cyclosporin A, phosphorylation assay for NFAT3, MUC5AC mRNA and protein measurement in ALI cultures of mouse tracheal epithelial cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacologic inhibitors only, no genetic knockdown of NFAT3, single lab\",\n      \"pmids\": [\"24583134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PGE2 induces MUC5AC expression in human intrahepatic biliary epithelial cells via EP4 receptor-p38 MAPK signaling; EP4 agonist increases and EP4 antagonist decreases MUC5AC expression, and p38 MAPK inhibitor reduces PGE2-induced MUC5AC expression.\",\n      \"method\": \"EP4 agonist/antagonist, p38 MAPK inhibitor, LPS stimulation with TLR4 antagonist and NF-kappaB inhibitor in HIBECs; bile samples from hepatolithiasis patients\",\n      \"journal\": \"Annals of hepatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacologic receptor/pathway inhibition only, no genetic knockdown, single lab\",\n      \"pmids\": [\"23619266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ITGB4 deficiency in airway epithelial cells induces MUC5AC overexpression through the EGFR/ERK/c-Jun pathway; EGFR inhibitors prevent mucus hypersecretion and MUC5AC overexpression in ITGB4-deficient mice after RSV infection.\",\n      \"method\": \"ITGB4 siRNA knockdown in HBE cells, ITGB4-deficient mice, RSV infection, EGFR inhibitor treatment, ERK/c-Jun pathway Western blot\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA in vitro + genetic KO mouse in vivo + EGFR inhibitor rescue, single lab\",\n      \"pmids\": [\"34975337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Spleen tyrosine kinase (SYK) induces MUC5AC expression in human airway epithelial cells via ERK2 and p38 MAPK signaling pathways; ERK2 siRNA and p38 MAPK siRNA each block SYK-induced MUC5AC expression.\",\n      \"method\": \"ERK1/2 inhibitor U0126, p38 inhibitor SB203580, ERK2 siRNA, p38 MAPK siRNA, SYK stimulation in NCI-H292 and primary human nasal epithelial cells\",\n      \"journal\": \"American journal of rhinology & allergy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — siRNA knockdown of downstream effectors only, no direct SYK knockout, single lab\",\n      \"pmids\": [\"26980390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Oxidative stress induces MUC5AC expression in airway epithelial cells via a mitochondrial damage-dependent STING (stimulator of interferon genes) pathway; STING knockout suppresses H2O2-induced MUC5AC expression, while cGAS knockout does not.\",\n      \"method\": \"STING and cGAS CRISPR knockout cells, hydrogen peroxide treatment, mitochondrial antioxidants, cytosolic mitochondrial DNA measurement in NCI-H292 and primary NHBECs\",\n      \"journal\": \"FASEB bioAdvances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO of STING vs cGAS distinguishing cGAS-independent STING mechanism, two cell types, single lab\",\n      \"pmids\": [\"37020748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MUC5AC interacts with Annexin A2 (ANXA2) in lung adenocarcinoma cells (identified by immunoprecipitation and proteomic analysis); this MUC5AC/ANXA2 signaling axis activates downstream matrix metalloproteases and facilitates ECM degradation to promote brain metastasis. A peptide inhibitor disrupting MUC5AC-ANXA2 interaction abrogates metastasis.\",\n      \"method\": \"Immunoprecipitation, proteomic analysis, MUC5AC depletion in brain-tropic cell lines, intracardiac injection brain metastasis models, peptide inhibitor\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + proteomics identifying MUC5AC-ANXA2 interaction + in vivo rescue with peptide inhibitor, single lab\",\n      \"pmids\": [\"38825648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NOTCH3 intracellular domain (NICD3) regulates MUC5AC (and MUC2) expression by directly recruiting SMARCA4 (BRG1/transcription activator); NOTCH3 controls MUC5AC transcription in a SMARCA4-dependent manner in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation of NICD3 and SMARCA4, RNA sequencing for target gene identification, functional assays in CRC cells\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying protein-protein interaction + RNA-seq + functional validation, single lab\",\n      \"pmids\": [\"35900231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MUC5AC contains polymorphic variable number tandem repeats (VNTRs) with cysteine-rich domain and VNTR copy-number variation defining 30 allelic variants encoding 16 distinct proteins (5,249-6,325 aa). Long-read sequencing and haplotype analysis reveal three phylogenetic clades (H1, H2, H3) with signatures of positive selection in East Asians and balancing selection in Europeans.\",\n      \"method\": \"Long-read sequencing and assembly of 206 human and 20 NHP haplotypes, Locityper genotyping of 2,600 samples from 1000 Genomes Project, Tajima's D and linkage disequilibrium analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — structural/genetic characterization without functional validation of specific variants\",\n      \"pmids\": [\"38991590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MUC5AC gene organization was fully elucidated: the 5' region encodes a signal peptide, four pro-von Willebrand factor-like D domains (D1, D2, D', D3), and the central region contains 9 cysteine-rich domains interspersed with serine/threonine/proline-rich domains and four tandem repeat arrays (TR1-TR4). Length polymorphism is due to variable numbers of tandem repeats in TR1 and TR4.\",\n      \"method\": \"Full-length cDNA sequencing, Southern blot analysis for allelic variations\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Strong — sequence/structural characterization, no functional experiments; replicated conceptually by subsequent structural studies\",\n      \"pmids\": [\"11535137\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MUC5AC is a gel-forming secreted mucin whose expression is regulated by multiple converging signaling pathways in airway and other epithelial cells—including NF-kappaB, EGFR/TACE/TGF-alpha, STAT6, ERK/MAPK, Notch, DUOX1-ROS, and autophagy/JNK/c-Jun cascades downstream of stimuli such as IL-1beta, IL-13, IL-17A, neutrophil elastase, and cigarette smoke—whose biosynthesis requires C-mannosylation of Cys subdomains in the ER for proper folding and secretion, whose mucosal function includes spatially aligning mucociliary transport and providing a barrier against luminal bacteria, and which in cancer contexts interacts physically with CD44 (activating Src), ANXA2 (activating MMPs for metastasis), and undergoes ST6GalNAc-I-mediated sialylation to promote tumor progression and immune evasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MUC5AC is a large gel-forming secreted mucin built from pro-von Willebrand factor-like D domains, cysteine-rich subdomains, and serine/threonine/proline-rich tandem-repeat arrays whose copy-number polymorphism underlies extensive allelic variation [#39]. Its biosynthesis requires C-mannosylation at WXXW motifs within the Cys1 and Cys5 subdomains in the endoplasmic reticulum, a modification needed for proper folding and ER export [#3]. At mucosal surfaces MUC5AC performs distinct protective functions: it spatially coordinates mucociliary transport on airway epithelium, such that its loss produces discoordinated rather than reduced transport [#24], and in the gut it limits bacterial contact with and translocation across the colonic epithelium, protecting against experimental colitis [#25]. MUC5AC transcription is a convergence point for many epithelial signaling cascades, dominated by EGFR activation triggered by TACE-mediated cleavage of pro-TGF-alpha downstream of DUOX1-generated ROS, microbial serine proteases, and muscarinic M3 receptor signaling [#0, #7, #10], by NF-kappaB acting both directly and through HIF-1alpha [#1, #15], and by STAT6, Notch, and MAPK-dependent inputs from type 2 and IL-17 cytokines [#11, #13, #14]. In cancer, MUC5AC acts beyond a secreted barrier: it physically engages CD44 to activate Src and drives colorectal tumor invasion and chemoresistance [#20], binds ANXA2 to activate matrix metalloproteases and promote brain metastasis [#36], undergoes ST6GalNAc-I-mediated STn sialylation that supports migration and metastasis [#23], and is required for KRAS-driven lung adenocarcinoma and for suppression of anti-tumor neutrophil immunity in pancreatic cancer [#21, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing the domain architecture of MUC5AC defined it as a von Willebrand factor-type gel-forming mucin and explained the molecular basis of its length polymorphism.\",\n      \"evidence\": \"Full-length cDNA sequencing and Southern blot of allelic variants\",\n      \"pmids\": [\"11535137\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional consequences assigned to individual domains\", \"Tandem-repeat polymorphism not linked to phenotype\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying C-mannosylation of the Cys subdomains answered how MUC5AC achieves proper folding and ER export, linking a specific co-translational glycosylation to secretion competence.\",\n      \"evidence\": \"WXXW mutagenesis, pulse-chase, lectin binding, and C-mannosylation-defective CHO-Lec35.1 cells with GFP-tagged subdomains\",\n      \"pmids\": [\"14718370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Done on isolated Cys subdomains, not full-length mucin\", \"Enzyme responsible for C-mannosylation not identified\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The DUOX1/ROS \\u2192 TACE \\u2192 pro-TGF-alpha \\u2192 EGFR cascade established a unifying oxidant-driven route by which airway stimuli converge on MUC5AC transcription.\",\n      \"evidence\": \"siRNA, ROS scavengers, NADPH oxidase and TACE inhibitors with PMA/neutrophil elastase in HBE and NCI-H292 cells\",\n      \"pmids\": [\"15640347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors terminal to EGFR not defined here\", \"Single airway context\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Reporter and in vivo work showed SMAD4 and HIF-1alpha bind conserved Muc5ac promoter motifs required for activity, and that Muc5ac is the dominant induced mucin in allergic airways.\",\n      \"evidence\": \"OVA mouse model plus luciferase promoter mutagenesis in a Clara cell line\",\n      \"pmids\": [\"17463395\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream activators of SMAD4/HIF-1alpha at the promoter not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"ChIP and reporter assays mapped a specific NF-kappaB (p50) site in the MUC5AC promoter, establishing direct cytokine-driven transcriptional control by IL-1beta and IL-17A.\",\n      \"evidence\": \"Reporter assays, p65 siRNA, NF-kappaB inhibitor, and ChIP in primary NHBE and HBE1 cells\",\n      \"pmids\": [\"19841186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cooperation with other promoter factors not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Microbial serine proteases and EGFR-Notch crosstalk were shown to feed the EGFR axis, broadening the range of stimuli that activate MUC5AC via TACE and amplifying signaling through reciprocal Notch-EGFR loops.\",\n      \"evidence\": \"Protease and TACE inhibitors, siRNA, neutralizing antibodies (Aspergillus); gamma-secretase inhibitors, Notch1 siRNA, NICD overexpression (Notch) in NCI-H292 and primary HBE cells\",\n      \"pmids\": [\"21685325\", \"21622856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pathway dissections\", \"Quantitative contribution relative to other inputs unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defining the STAT6 \\u2192 TMEM16A \\u2192 ERK route and Lyn-mediated negative regulation of STAT6 clarified how type 2 cytokine signaling is tuned at the MUC5AC promoter.\",\n      \"evidence\": \"STAT6 inhibition and TMEM16A siRNA (IL-13); Lyn gain/loss-of-function with ChIP for STAT6 binding in 16HBE and OVA mice\",\n      \"pmids\": [\"27588910\", \"28205598\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell lines/labs\", \"Integration with NF-kappaB inputs not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Co-IP and CRISPR knockout established MUC5AC as an active cancer-promoting protein through physical CD44 engagement and Src activation, beyond its role as a secreted barrier.\",\n      \"evidence\": \"Reciprocal co-IP, CRISPR/Cas9 knockout, in vitro and orthotopic in vivo assays in colorectal cancer cells\",\n      \"pmids\": [\"32098629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface not mapped\", \"Generalizability beyond CRC unestablished\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic knockout in the colon demonstrated that MUC5AC's barrier function operates by excluding bacteria, with antibiotics rescuing the colitis phenotype.\",\n      \"evidence\": \"Muc5ac-/- mice, DSS colitis, bacterial translocation assays, 16S sequencing, antibiotic rescue\",\n      \"pmids\": [\"32385500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of bacterial exclusion at molecular level not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Separate CRISPR knockout of MUC5AC and MUC5B in human airway cultures showed MUC5AC uniquely coordinates the spatial alignment of mucociliary transport rather than its overall magnitude.\",\n      \"evidence\": \"CRISPR-deficient human airway ALI cultures with quantitative transport measurement\",\n      \"pmids\": [\"36427316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biophysical basis of coordination not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of the MUC5AC-ANXA2 axis and ST6GalNAc-I-mediated STn sialylation extended MUC5AC's tumor-promoting mechanism to MMP activation/metastasis and glycan-driven progression.\",\n      \"evidence\": \"Co-IP/proteomics and peptide inhibitor in brain-metastasis models (ANXA2); MUC5AC STn immunoprecipitation and ST6GalNAc-I CRISPR knockout in metastasis models (sialylation)\",\n      \"pmids\": [\"38825648\", \"33792183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies\", \"Interaction interfaces and glycosite specificity incompletely defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many converging transcriptional inputs are integrated at the native MUC5AC locus, and whether VNTR allelic variants confer functionally distinct mucin properties, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No combinatorial promoter logic established across the cited pathways\", \"Functional consequences of the 16 allelic protein variants untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [24, 25, 39]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [24, 25]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD44\", \"ANXA2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}