DUOX1 (dual oxidase 1) is a large, multi-pass membrane flavocytochrome that generates extracellular hydrogen peroxide. Its cytosolic dehydrogenase domain binds NADPH and FAD and passes electrons through two hemes in the 24-helix transmembrane layer to oxygen on the outer face of the membrane, producing H2O2 rather than superoxide. Activity is switched on by calcium through EF-hand modules in the long intracellular loop. The enzyme is obligately paired with the maturation factor DUOXA1, with which it folds and is N-glycosylated in the endoplasmic reticulum and then travels to the cell surface; in polarized epithelia the complex is sorted to the apical plasma membrane, and in migrating cells it concentrates at the leading edge. A large N-terminal peroxidase-homology domain faces the extracellular space, but in the human protein it lacks the heme-ligating histidine, binds no heme and has no intrinsic peroxidase activity, so its role is unresolved; the nematode orthologue's equivalent domain does bind heme and cross-links cuticle tyrosines. DUOX1 is expressed most strongly in airway surface epithelium and in thyrocytes. The H2O2 it releases is the co-substrate for extracellular peroxidases (lactoperoxidase at mucosal surfaces, thyroid peroxidase in the thyroid follicle, where DUOX2 is the dominant paralog), and also acts as a diffusible signal that drives EGFR/ERK and NF-kB-dependent epithelial responses to bacterial stimuli, antiviral defense via hypothiocyanite, cell motility and wound closure.
Definition: Catalysis of the reaction: NAADPH + O2 + H+ = NAADP+ + H2O2. NAADPH is the reduced form of nicotinic acid adenine dinucleotide phosphate, the calcium-mobilising second messenger; its oxidation by a NOX/DUOX-family flavocytochrome regenerates NAADP.
Justification: UniProt records this catalytic activity for human DUOX1 with experimental evidence (Rhea:86235) from the study that identified NOX and DUOX enzymes as NAADP-forming, and no GO molecular function covers the NAADPH substrate: GO:0016174 is defined on NAD(P)H. No annotation is proposed here; the entry records the ontology gap.
Parent term: oxidoreductase activity
Mappings:
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004601 peroxidase activity | IDA NOT PMID:19460756 Caenorhabditis elegans and human dual oxidase 1 (DUOX1) "per... | ACCEPT | Summary: Keep the NOT annotation. Two independent experiments agree that the N-terminal peroxidase-homology domain (PHD) of human DUOX1 is not a working peroxidase: the purified isolated domain binds no heme and has no peroxidase activity, and the cryo-EM structure of the full-length DUOX1-DUOXA1 complex shows the heme-ligating histidine absent and no heme density in the PHD. Reason: The negation is domain-specific and does not conflict with the heme binding annotated elsewhere in this review: the two hemes of DUOX1 are in the transmembrane NOX core, not in the PHD. The one contrary report, in which an E. coli-expressed h-Duox peroxidase domain cross-linked tyrosine ethyl ester (PMID:11514595), is the conflict UniProt records in its CAUTION line; it predates both direct heme measurements and is not a reason to drop a negation that two later, more direct assays support. The C. elegans orthologue behaves differently (its PHD binds heme covalently and has modest peroxidase activity), which is a property of that lineage and not of human DUOX1. Supporting Evidence: PMID:19460756 the isolated hDUOX1(1-593) does not bind heme and has no intrinsic peroxidase activity PMID:33420071 key residues for heme binding, such as the heme ligand histidine, are missing in the PHD of hDUOX1 PMID:33420071 we did not observe any heme density in the structure of hDUOX1 PHD, suggesting PHD is probably not enzymatic functional in term of peroxidase activity PMID:19460756 In contrast, CeDUOX1(1-589) binds heme covalently, exhibits a modest peroxidase activity, but does not oxidize bromide ion. file:human/DUOX1/DUOX1-uniprot.txt CAUTION: The role of the N-terminal peroxidase-like domain is unclear. file:human/DUOX1/DUOX1-deep-research-manual.md The extracellular N-terminal region has a peroxidase-like fold but lacks the intrinsic peroxidase activity of a conventional mammalian peroxidase. |
| GO:0005509 calcium ion binding | IDA PMID:33420071 Structures of human dual oxidase 1 complex in low-calcium an... | ACCEPT | Summary: Calcium binding is part of the catalytic mechanism: DUOX1 carries EF-hand modules in its long intracellular loop, calcium is resolved in the cryo-EM structure, and H2O2 production by the reconstituted DUOX1-DUOXA1 complex is calcium-activated. Reason: Core. Calcium occupancy of the EF-hands is the switch that converts the complex to the active state, so this is a direct component of the oxidase mechanism rather than an incidental ligand. The InterPro EF-hand (IPR002048) mapping on the IEA row agrees with the structural evidence. Supporting Evidence: PMID:33420071 the functional DUOX protein has an additional large N-terminal extracellular peroxidase homology domain (PHD) and a long intracellular loop 0 containing two EF-hand domains, and it requires an auxiliary DUOXA protein for proper function PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:33420071 their activities are regulated by intracellular calcium concentrations file:human/DUOX1/DUOX1-uniprot.txt ACTIVITY REGULATION: The NADPH oxidase activity is calcium-dependent |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: Calcium binding is part of the catalytic mechanism: DUOX1 carries EF-hand modules in its long intracellular loop, calcium is resolved in the cryo-EM structure, and H2O2 production by the reconstituted DUOX1-DUOXA1 complex is calcium-activated. Reason: Core. Calcium occupancy of the EF-hands is the switch that converts the complex to the active state, so this is a direct component of the oxidase mechanism rather than an incidental ligand. The InterPro EF-hand (IPR002048) mapping on the IEA row agrees with the structural evidence. Supporting Evidence: PMID:33420071 the functional DUOX protein has an additional large N-terminal extracellular peroxidase homology domain (PHD) and a long intracellular loop 0 containing two EF-hand domains, and it requires an auxiliary DUOXA protein for proper function PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:33420071 their activities are regulated by intracellular calcium concentrations file:human/DUOX1/DUOX1-uniprot.txt ACTIVITY REGULATION: The NADPH oxidase activity is calcium-dependent |
| GO:0005515 protein binding | IPI PMID:19339556 Heterodimerization controls localization of Duox-DuoxA NADPH... | MODIFY | Summary: The interaction recorded here is with DUOXA1 isoform (UniProtKB:Q1HG43-2), the DUOX maturation factor with which DUOX1 forms an obligate heterodimer; bare protein binding states none of that. Reason: Bare GO:0005515 carries no functional information, so under the repo protein-binding policy it is replaced rather than kept. The informative term for this interaction is protein heterodimerization activity: DUOX1 and DUOXA1 form functional heterodimers (two of which assemble into the heterotetramer resolved by cryo-EM), heterodimerization is a prerequisite for ROS production, and the partner also determines where the oxidase is delivered. Removing the generic row does not deny the reported interaction, and the complex membership is separately captured by GO:0043020. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:19339556 Duox proteins form functional heterodimers with their respective DuoxA subunits, in close analogy to the phagocyte NADPH oxidase. PMID:19339556 Characterization of novel DuoxA1 isoforms and mispaired Duox-DuoxA complexes revealed that heterodimerization is a prerequisite for reactive oxygen species production. |
| GO:0005515 protein binding | IPI PMID:19339556 Heterodimerization controls localization of Duox-DuoxA NADPH... | MODIFY | Summary: The interaction recorded here is with DUOXA1 isoform (UniProtKB:Q1HG43-3), the DUOX maturation factor with which DUOX1 forms an obligate heterodimer; bare protein binding states none of that. Reason: Bare GO:0005515 carries no functional information, so under the repo protein-binding policy it is replaced rather than kept. The informative term for this interaction is protein heterodimerization activity: DUOX1 and DUOXA1 form functional heterodimers (two of which assemble into the heterotetramer resolved by cryo-EM), heterodimerization is a prerequisite for ROS production, and the partner also determines where the oxidase is delivered. Removing the generic row does not deny the reported interaction, and the complex membership is separately captured by GO:0043020. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:19339556 Duox proteins form functional heterodimers with their respective DuoxA subunits, in close analogy to the phagocyte NADPH oxidase. PMID:19339556 Characterization of novel DuoxA1 isoforms and mispaired Duox-DuoxA complexes revealed that heterodimerization is a prerequisite for reactive oxygen species production. |
| GO:0005515 protein binding | IPI PMID:19339556 Heterodimerization controls localization of Duox-DuoxA NADPH... | MODIFY | Summary: The interaction recorded here is with DUOXA2 (UniProtKB:Q1HG44), the DUOX maturation factor with which DUOX1 forms an obligate heterodimer; bare protein binding states none of that. Reason: Bare GO:0005515 carries no functional information, so under the repo protein-binding policy it is replaced rather than kept. The informative term for this interaction is protein heterodimerization activity: DUOX1 and DUOXA1 form functional heterodimers (two of which assemble into the heterotetramer resolved by cryo-EM), heterodimerization is a prerequisite for ROS production, and the partner also determines where the oxidase is delivered. Removing the generic row does not deny the reported interaction, and the complex membership is separately captured by GO:0043020. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:19339556 Duox proteins form functional heterodimers with their respective DuoxA subunits, in close analogy to the phagocyte NADPH oxidase. PMID:19339556 Characterization of novel DuoxA1 isoforms and mispaired Duox-DuoxA complexes revealed that heterodimerization is a prerequisite for reactive oxygen species production. |
| GO:0005515 protein binding | IPI PMID:33420071 Structures of human dual oxidase 1 complex in low-calcium an... | MODIFY | Summary: The interaction recorded here is with DUOXA1 (UniProtKB:Q1HG43), the DUOX maturation factor with which DUOX1 forms an obligate heterodimer; bare protein binding states none of that. Reason: Bare GO:0005515 carries no functional information, so under the repo protein-binding policy it is replaced rather than kept. The informative term for this interaction is protein heterodimerization activity: DUOX1 and DUOXA1 form functional heterodimers (two of which assemble into the heterotetramer resolved by cryo-EM), heterodimerization is a prerequisite for ROS production, and the partner also determines where the oxidase is delivered. Removing the generic row does not deny the reported interaction, and the complex membership is separately captured by GO:0043020. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:33420071 the functional DUOX protein has an additional large N-terminal extracellular peroxidase homology domain (PHD) and a long intracellular loop 0 containing two EF-hand domains, and it requires an auxiliary DUOXA protein for proper function file:human/DUOX1/DUOX1-uniprot.txt SUBUNIT: Heterotetramer with DUOXA1 consisting of 2 DUOX1-DUOXA1 |
| GO:0005515 protein binding | IPI PMID:39126279 The NADPH oxidases DUOX1 and DUOX2 are sorted to the apical ... | MODIFY | Summary: The interaction recorded here is with DUOXA1 (UniProtKB:Q1HG43), the DUOX maturation factor with which DUOX1 forms an obligate heterodimer; bare protein binding states none of that. Reason: Bare GO:0005515 carries no functional information, so under the repo protein-binding policy it is replaced rather than kept. The informative term for this interaction is protein heterodimerization activity: DUOX1 and DUOXA1 form functional heterodimers (two of which assemble into the heterotetramer resolved by cryo-EM), heterodimerization is a prerequisite for ROS production, and the partner also determines where the oxidase is delivered. Removing the generic row does not deny the reported interaction, and the complex membership is separately captured by GO:0043020. Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:39126279 DUOX1 and DUOX2 are correctly sorted to the apical membrane via the membrane-spanning DUOX maturation proteins DUOXA1 and DUOXA2, respectively, when co-expressed in MDCK epithelial cells PMID:39126279 Impairment of N-glycosylation of DUOXA1 results in mistargeting of DUOX1 to the basolateral membrane. |
| GO:0005783 endoplasmic reticulum | IDA PMID:19339556 Heterodimerization controls localization of Duox-DuoxA NADPH... | KEEP AS NON CORE | Summary: Endoplasmic reticulum localization reflects DUOX1 maturation rather than the site of its activity: the oxidase is N-glycosylated and oxidatively folded in the ER and only reaches the plasma membrane after pairing with DUOXA1. Reason: True but peripheral. The immature, partially glycosylated DUOX protein is ER-resident and is catalytically different from the mature enzyme (in the DUOX2 experiments it leaks superoxide rather than releasing H2O2), and ER-to-Golgi transport of DUOX1 requires physical interaction with DUOXA1. The curator-observed ER staining is not disputed; it is simply not where DUOX1 does its work. Supporting Evidence: PMID:15972824 the partially glycosylated form of Duox2, located in the endoplasmic reticulum, generates superoxide in a calcium-dependent manner PMID:25761904 The oxidative folding of DUOX2 that takes place in the endoplasmic reticulum (ER) appears to be a key event in the trafficking of the DUOX2/DUOXA2 complex |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The plasma membrane is where the mature DUOX1-DUOXA1 complex acts, releasing H2O2 to the extracellular side. Reason: Core, and not merely an under-specification of the apical plasma membrane annotated elsewhere: in polarized epithelia the complex is apical, but in migrating cells functional DUOX1 is at the leading edge, and in heterologous cells it is delivered to the basolateral surface when DUOXA1 N-glycosylation is lost. Plasma membrane is the statement that holds across all of these. The IBA row rests on PAINT node PTN001735877, whose seeds include this protein together with NOX/DUOX and plant and yeast relatives, which is the right level of generality for a family-wide inference. Supporting Evidence: PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. PMID:39126279 The membrane-integrated NADPH oxidases DUOX1 and DUOX2 are recruited to the apical plasma membrane in epithelial cells to release hydrogen peroxide, thereby playing crucial roles in various functions such as thyroid hormone synthesis and host defense. PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0005886 plasma membrane | IDA PMID:19339556 Heterodimerization controls localization of Duox-DuoxA NADPH... | ACCEPT | Summary: The plasma membrane is where the mature DUOX1-DUOXA1 complex acts, releasing H2O2 to the extracellular side. Reason: Core, and not merely an under-specification of the apical plasma membrane annotated elsewhere: in polarized epithelia the complex is apical, but in migrating cells functional DUOX1 is at the leading edge, and in heterologous cells it is delivered to the basolateral surface when DUOXA1 N-glycosylation is lost. Plasma membrane is the statement that holds across all of these. The IBA row rests on PAINT node PTN001735877, whose seeds include this protein together with NOX/DUOX and plant and yeast relatives, which is the right level of generality for a family-wide inference. Supporting Evidence: PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. PMID:39126279 The membrane-integrated NADPH oxidases DUOX1 and DUOX2 are recruited to the apical plasma membrane in epithelial cells to release hydrogen peroxide, thereby playing crucial roles in various functions such as thyroid hormone synthesis and host defense. PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: The plasma membrane is where the mature DUOX1-DUOXA1 complex acts, releasing H2O2 to the extracellular side. Reason: Core, and not merely an under-specification of the apical plasma membrane annotated elsewhere: in polarized epithelia the complex is apical, but in migrating cells functional DUOX1 is at the leading edge, and in heterologous cells it is delivered to the basolateral surface when DUOXA1 N-glycosylation is lost. Plasma membrane is the statement that holds across all of these. The IBA row rests on PAINT node PTN001735877, whose seeds include this protein together with NOX/DUOX and plant and yeast relatives, which is the right level of generality for a family-wide inference. Supporting Evidence: PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. PMID:39126279 The membrane-integrated NADPH oxidases DUOX1 and DUOX2 are recruited to the apical plasma membrane in epithelial cells to release hydrogen peroxide, thereby playing crucial roles in various functions such as thyroid hormone synthesis and host defense. PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-209815 | ACCEPT | Summary: The plasma membrane is where the mature DUOX1-DUOXA1 complex acts, releasing H2O2 to the extracellular side. Reason: Core, and not merely an under-specification of the apical plasma membrane annotated elsewhere: in polarized epithelia the complex is apical, but in migrating cells functional DUOX1 is at the leading edge, and in heterologous cells it is delivered to the basolateral surface when DUOXA1 N-glycosylation is lost. Plasma membrane is the statement that holds across all of these. The IBA row rests on PAINT node PTN001735877, whose seeds include this protein together with NOX/DUOX and plant and yeast relatives, which is the right level of generality for a family-wide inference. Supporting Evidence: PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. PMID:39126279 The membrane-integrated NADPH oxidases DUOX1 and DUOX2 are recruited to the apical plasma membrane in epithelial cells to release hydrogen peroxide, thereby playing crucial roles in various functions such as thyroid hormone synthesis and host defense. PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-209840 | ACCEPT | Summary: The plasma membrane is where the mature DUOX1-DUOXA1 complex acts, releasing H2O2 to the extracellular side. Reason: Core, and not merely an under-specification of the apical plasma membrane annotated elsewhere: in polarized epithelia the complex is apical, but in migrating cells functional DUOX1 is at the leading edge, and in heterologous cells it is delivered to the basolateral surface when DUOXA1 N-glycosylation is lost. Plasma membrane is the statement that holds across all of these. The IBA row rests on PAINT node PTN001735877, whose seeds include this protein together with NOX/DUOX and plant and yeast relatives, which is the right level of generality for a family-wide inference. Supporting Evidence: PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. PMID:39126279 The membrane-integrated NADPH oxidases DUOX1 and DUOX2 are recruited to the apical plasma membrane in epithelial cells to release hydrogen peroxide, thereby playing crucial roles in various functions such as thyroid hormone synthesis and host defense. PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-209925 | ACCEPT | Summary: The plasma membrane is where the mature DUOX1-DUOXA1 complex acts, releasing H2O2 to the extracellular side. Reason: Core, and not merely an under-specification of the apical plasma membrane annotated elsewhere: in polarized epithelia the complex is apical, but in migrating cells functional DUOX1 is at the leading edge, and in heterologous cells it is delivered to the basolateral surface when DUOXA1 N-glycosylation is lost. Plasma membrane is the statement that holds across all of these. The IBA row rests on PAINT node PTN001735877, whose seeds include this protein together with NOX/DUOX and plant and yeast relatives, which is the right level of generality for a family-wide inference. Supporting Evidence: PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. PMID:39126279 The membrane-integrated NADPH oxidases DUOX1 and DUOX2 are recruited to the apical plasma membrane in epithelial cells to release hydrogen peroxide, thereby playing crucial roles in various functions such as thyroid hormone synthesis and host defense. PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-209973 | ACCEPT | Summary: The plasma membrane is where the mature DUOX1-DUOXA1 complex acts, releasing H2O2 to the extracellular side. Reason: Core, and not merely an under-specification of the apical plasma membrane annotated elsewhere: in polarized epithelia the complex is apical, but in migrating cells functional DUOX1 is at the leading edge, and in heterologous cells it is delivered to the basolateral surface when DUOXA1 N-glycosylation is lost. Plasma membrane is the statement that holds across all of these. The IBA row rests on PAINT node PTN001735877, whose seeds include this protein together with NOX/DUOX and plant and yeast relatives, which is the right level of generality for a family-wide inference. Supporting Evidence: PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. PMID:39126279 The membrane-integrated NADPH oxidases DUOX1 and DUOX2 are recruited to the apical plasma membrane in epithelial cells to release hydrogen peroxide, thereby playing crucial roles in various functions such as thyroid hormone synthesis and host defense. PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-350901 | ACCEPT | Summary: The plasma membrane is where the mature DUOX1-DUOXA1 complex acts, releasing H2O2 to the extracellular side. Reason: Core, and not merely an under-specification of the apical plasma membrane annotated elsewhere: in polarized epithelia the complex is apical, but in migrating cells functional DUOX1 is at the leading edge, and in heterologous cells it is delivered to the basolateral surface when DUOXA1 N-glycosylation is lost. Plasma membrane is the statement that holds across all of these. The IBA row rests on PAINT node PTN001735877, whose seeds include this protein together with NOX/DUOX and plant and yeast relatives, which is the right level of generality for a family-wide inference. Supporting Evidence: PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. PMID:39126279 The membrane-integrated NADPH oxidases DUOX1 and DUOX2 are recruited to the apical plasma membrane in epithelial cells to release hydrogen peroxide, thereby playing crucial roles in various functions such as thyroid hormone synthesis and host defense. PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5693681 | ACCEPT | Summary: The plasma membrane is where the mature DUOX1-DUOXA1 complex acts, releasing H2O2 to the extracellular side. Reason: Core, and not merely an under-specification of the apical plasma membrane annotated elsewhere: in polarized epithelia the complex is apical, but in migrating cells functional DUOX1 is at the leading edge, and in heterologous cells it is delivered to the basolateral surface when DUOXA1 N-glycosylation is lost. Plasma membrane is the statement that holds across all of these. The IBA row rests on PAINT node PTN001735877, whose seeds include this protein together with NOX/DUOX and plant and yeast relatives, which is the right level of generality for a family-wide inference. Supporting Evidence: PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. PMID:39126279 The membrane-integrated NADPH oxidases DUOX1 and DUOX2 are recruited to the apical plasma membrane in epithelial cells to release hydrogen peroxide, thereby playing crucial roles in various functions such as thyroid hormone synthesis and host defense. PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0006590 thyroid hormone generation | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: DUOX1 performs a step of thyroid hormone synthesis: it generates the H2O2 that thyroid peroxidase consumes to iodinate thyroglobulin, and H2O2 supply is the limiting factor for that reaction. Reason: This is participation, not merely necessity, because DUOX1 itself catalyses the H2O2-forming half-reaction at the apical membrane of the thyrocyte rather than being a substrate of the pathway. It is non-core for DUOX1 specifically: DUOX2 is the dominant thyroid isoform and the gene in which biallelic loss causes congenital hypothyroidism, whereas DUOX1 is predominantly an airway enzyme. The UniPathway mapping behind the IEA therefore states something true but secondary for this paralog. Supporting Evidence: PMID:10806195 Two cDNAs encoding NADPH oxidases and constituting the thyroid H(2)O(2) generating system have been cloned. PMID:15062544 The limiting factor of this reaction is the supply of hydrogen peroxide. PMID:39126279 The membrane-integrated NADPH oxidases DUOX1 and DUOX2 are recruited to the apical plasma membrane in epithelial cells to release hydrogen peroxide, thereby playing crucial roles in various functions such as thyroid hormone synthesis and host defense. |
| GO:0006952 defense response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: DUOX1-derived H2O2 feeds extracellular peroxidases at mucosal surfaces, and this defensive role is conserved across the NOX/DUOX family. Reason: True and broadly supported, but kept as non-core because the more specific defense terms annotated elsewhere in this review (antiviral innate immune response, positive regulation of defense response to bacterium) say what DUOX1 actually contributes. The IBA sits at PAINT node PTN000239643 and lists this protein among its seeds, which is expected: the gene's own experimental evidence helped place the IBD, and the IBA then adds that the role is inherited rather than lineage-specific. Supporting Evidence: PMID:19386603 Activation of the NADPH oxidase homolog dual oxidase 1 (DUOX1) within the airway epithelium represents a key mechanism of innate airway host defense, through enhanced production of H2O2 PMID:34168077 In primary human tracheobronchial epithelial cells, OSCN- is generated by LPO using DUOX1-derived H2O2 and inactivates several influenza strains in vitro. |
| GO:0006979 response to oxidative stress | IEA GO_REF:0000002 | REMOVE | Summary: This is an InterPro2GO mapping from the animal haem peroxidase signature IPR010255, which DUOX1 matches through its N-terminal peroxidase-homology domain. In human DUOX1 that domain binds no heme and has no peroxidase activity, and DUOX1 is a producer of reactive oxygen species rather than a participant in a response to oxidative stress. Reason: The domain that triggers the mapping is the one shown structurally and biochemically to lack the heme ligand and any peroxidase function in this protein, so the premise of the automatic inference fails here. Beyond that, the mapping inverts the biology: oxidant generation is not oxidant detoxification or sensing, and no experiment attributes an oxidative-stress response role to DUOX1. Removing an electronic mapping that is wrong on both counts leaves the gene's genuine ROS terms untouched. Supporting Evidence: PMID:33420071 key residues for heme binding, such as the heme ligand histidine, are missing in the PHD of hDUOX1 PMID:33420071 we did not observe any heme density in the structure of hDUOX1 PHD, suggesting PHD is probably not enzymatic functional in term of peroxidase activity PMID:19460756 the isolated hDUOX1(1-593) does not bind heme and has no intrinsic peroxidase activity |
| GO:0009615 response to virus | IEA GO_REF:0000117 | TOO GENERAL | Summary: Response to virus is true of DUOX1 but is entailed by the antiviral innate immune response term kept elsewhere in this review, which is what the evidence actually shows. Reason: GO:0140374 is a descendant of GO:0009615, and the experimental work (Duox1-null mice with impaired influenza clearance; LPO-generated hypothiocyanite from DUOX1-derived H2O2 inactivating influenza) supports the specific term. The ARBA row is not false and is not removed; it simply adds nothing beyond the more informative annotation. Supporting Evidence: PMID:34168077 Upon influenza airway challenge, Duox1-/- mice have enhanced mortality, morbidity, and impaired lung viral clearance. PMID:34168077 In primary human tracheobronchial epithelial cells, OSCN- is generated by LPO using DUOX1-derived H2O2 and inactivates several influenza strains in vitro. |
| GO:0009986 cell surface | IGI PMID:22814254 The type of DUOX-dependent ROS production is dictated by def... | KEEP AS NON CORE | Summary: Surface expression of DUOX1 in reconstituted cells depends on the DUOXA partner, which is what the genetic-interaction evidence shows. Reason: Correct but coarse: cell surface is the readout available in a non-polarized heterologous system, while the informative locations for DUOX1 are the plasma membrane and, in polarized epithelia, the apical plasma membrane, both annotated and accepted here. Kept rather than modified because the COS-7 experiments cannot distinguish an apical pool. Supporting Evidence: PMID:22814254 DUOX activator (DUOXA) proteins act as organizing elements for surface expression and activity of the DUOX enzymes. PMID:19339556 DuoxA subunits are responsible for targeting functional oxidases to distinct cellular compartments in lung epithelial cells |
| GO:0009986 cell surface | IGI PMID:22814254 The type of DUOX-dependent ROS production is dictated by def... | KEEP AS NON CORE | Summary: Surface expression of DUOX1 in reconstituted cells depends on the DUOXA partner, which is what the genetic-interaction evidence shows. Reason: Correct but coarse: cell surface is the readout available in a non-polarized heterologous system, while the informative locations for DUOX1 are the plasma membrane and, in polarized epithelia, the apical plasma membrane, both annotated and accepted here. Kept rather than modified because the COS-7 experiments cannot distinguish an apical pool. Supporting Evidence: PMID:22814254 DUOX activator (DUOXA) proteins act as organizing elements for surface expression and activity of the DUOX enzymes. PMID:19339556 DuoxA subunits are responsible for targeting functional oxidases to distinct cellular compartments in lung epithelial cells |
| GO:0016174 NAD(P)H oxidase H2O2-forming activity | EXP PMID:15972824 Dual oxidase-2 has an intrinsic Ca2+-dependent H2O2-generati... | ACCEPT | Summary: This is the core catalytic activity of DUOX1: NADPH-dependent, calcium-activated reduction of oxygen to hydrogen peroxide. Reason: Core. Membrane fractions from DUOX1-transfected cells show NADPH/Ca2+-dependent H2O2-generating activity, and the purified DUOX1-DUOXA1 complex reconstitutes calcium-activated, NADPH-dependent H2O2 production. The IBA is placed at PAINT node PTN000944147, the DUOX-specific node whose seeds include this protein alongside DUOX2 and the fly and nematode Duox proteins, so the phylogenetic and experimental statements agree. Supporting Evidence: PMID:15972824 The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca2+-dependent H2O2-generating activity. PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. |
| GO:0016174 NAD(P)H oxidase H2O2-forming activity | IBA GO_REF:0000033 | ACCEPT | Summary: This is the core catalytic activity of DUOX1: NADPH-dependent, calcium-activated reduction of oxygen to hydrogen peroxide. Reason: Core. Membrane fractions from DUOX1-transfected cells show NADPH/Ca2+-dependent H2O2-generating activity, and the purified DUOX1-DUOXA1 complex reconstitutes calcium-activated, NADPH-dependent H2O2 production. The IBA is placed at PAINT node PTN000944147, the DUOX-specific node whose seeds include this protein alongside DUOX2 and the fly and nematode Duox proteins, so the phylogenetic and experimental statements agree. Supporting Evidence: PMID:15972824 The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca2+-dependent H2O2-generating activity. PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. |
| GO:0016174 NAD(P)H oxidase H2O2-forming activity | IEA GO_REF:0000120 | ACCEPT | Summary: This is the core catalytic activity of DUOX1: NADPH-dependent, calcium-activated reduction of oxygen to hydrogen peroxide. Reason: Core. Membrane fractions from DUOX1-transfected cells show NADPH/Ca2+-dependent H2O2-generating activity, and the purified DUOX1-DUOXA1 complex reconstitutes calcium-activated, NADPH-dependent H2O2 production. The IBA is placed at PAINT node PTN000944147, the DUOX-specific node whose seeds include this protein alongside DUOX2 and the fly and nematode Duox proteins, so the phylogenetic and experimental statements agree. Supporting Evidence: PMID:15972824 The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca2+-dependent H2O2-generating activity. PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. |
| GO:0016174 NAD(P)H oxidase H2O2-forming activity | NAS PMID:10806195 Cloning of two human thyroid cDNAs encoding new members of t... | ACCEPT | Summary: This is the core catalytic activity of DUOX1: NADPH-dependent, calcium-activated reduction of oxygen to hydrogen peroxide. Reason: Core. Membrane fractions from DUOX1-transfected cells show NADPH/Ca2+-dependent H2O2-generating activity, and the purified DUOX1-DUOXA1 complex reconstitutes calcium-activated, NADPH-dependent H2O2 production. The IBA is placed at PAINT node PTN000944147, the DUOX-specific node whose seeds include this protein alongside DUOX2 and the fly and nematode Duox proteins, so the phylogenetic and experimental statements agree. Supporting Evidence: PMID:15972824 The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca2+-dependent H2O2-generating activity. PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. |
| GO:0016174 NAD(P)H oxidase H2O2-forming activity | TAS Reactome:R-HSA-5693681 | ACCEPT | Summary: This is the core catalytic activity of DUOX1: NADPH-dependent, calcium-activated reduction of oxygen to hydrogen peroxide. Reason: Core. Membrane fractions from DUOX1-transfected cells show NADPH/Ca2+-dependent H2O2-generating activity, and the purified DUOX1-DUOXA1 complex reconstitutes calcium-activated, NADPH-dependent H2O2 production. The IBA is placed at PAINT node PTN000944147, the DUOX-specific node whose seeds include this protein alongside DUOX2 and the fly and nematode Duox proteins, so the phylogenetic and experimental statements agree. Supporting Evidence: PMID:15972824 The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca2+-dependent H2O2-generating activity. PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:33420071 Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. |
| GO:0016175 superoxide-generating NAD(P)H oxidase activity | IBA GO_REF:0000033 | MODIFY | Summary: The mature DUOX1-DUOXA1 complex releases hydrogen peroxide, not superoxide; the superoxide-generating activity belongs to the NOX branch of the family. Reason: This is a lateral correction within the family, argued from the phylogeny rather than from similarity. PAINT placed GO:0016175 at PTN000239643, the deep NOX/DUOX ancestor seeded by NOX1, NOX2 (CYBB), NOX4, NOX5 and their rodent and amoebal relatives, and placed the H2O2-forming activity GO:0016174 separately at the DUOX-specific node PTN000944147, whose seeds include DUOX1 itself. The experimental record agrees with that split: mature DUOX does not release superoxide but H2O2, superoxide leakage is seen only from the immature ER form of DUOX2 or when the DUOXA2 N-terminus is altered, and the C-terminus of DUOXA1 directs DUOX1 to H2O2 output. The claim is not false of the family, but it is false of this protein, so the replacement is the sibling term the DUOX node carries. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000239643 · deep NOX/DUOX ancestral node carrying the IBD SUPPORTS SOURCE BUT NOT TARGET Node seeded by NOX-branch members (NOX1, CYBB/NOX2, NOX4, NOX5 and rodent and amoebal homologues); superoxide output is a property of that branch, not of the DUOX clade below it. PANTHER:PTN000944147 · DUOX-specific node carrying the H2O2-forming IBD SUPPORTS TRANSFER Seeds include UniProtKB:Q9NRD9 itself together with DUOX2 and the fly and nematode Duox proteins; PAINT placed NAD(P)H oxidase H2O2-forming activity here, which is the term this row should carry. UniProtKB:P04839 · CYBB/NOX2 (human) SUPPORTS SOURCE BUT NOT TARGET Experimentally a superoxide generator; the seed is sound for the node and wrong for DUOX1. Proposed replacements: NAD(P)H oxidase H2O2-forming activity Supporting Evidence: PMID:15972824 it was shown that mature thyroid NADPH oxidase does not release O2*- but H2O2 PMID:15972824 the partially glycosylated form of Duox2, located in the endoplasmic reticulum, generates superoxide in a calcium-dependent manner PMID:22814254 We have shown that the COOH-terminal end of DUOXA1 is responsible for DUOX1-dependent H(2)O(2) generation. |
| GO:0016324 apical plasma membrane | EXP PMID:15210697 NADPH oxidase-dependent acid production in airway epithelial... | ACCEPT | Summary: In polarized epithelia DUOX1 is delivered to the apical plasma membrane, where it releases H2O2 into the lumen or airway surface liquid. Reason: Core location. Apical staining is seen in primary human tracheal epithelium, and in MDCK cells DUOX1 is sorted apically via N-glycosylated DUOXA1, with mistargeting to the basolateral membrane when that glycosylation is lost. This is the specific, functionally relevant refinement of the plasma membrane annotation. Supporting Evidence: PMID:15210697 Anti-Duox antibody staining resulted in prominent apical staining in hTE but no significant staining in Calu-3. PMID:39126279 DUOX1 and DUOX2 are correctly sorted to the apical membrane via the membrane-spanning DUOX maturation proteins DUOXA1 and DUOXA2, respectively, when co-expressed in MDCK epithelial cells PMID:39126279 Impairment of N-glycosylation of DUOXA1 results in mistargeting of DUOX1 to the basolateral membrane. |
| GO:0016324 apical plasma membrane | EXP PMID:34784249 Dual NADPH oxidases DUOX1 and DUOX2 synthesize NAADP and are... | ACCEPT | Summary: In polarized epithelia DUOX1 is delivered to the apical plasma membrane, where it releases H2O2 into the lumen or airway surface liquid. Reason: Core location. Apical staining is seen in primary human tracheal epithelium, and in MDCK cells DUOX1 is sorted apically via N-glycosylated DUOXA1, with mistargeting to the basolateral membrane when that glycosylation is lost. This is the specific, functionally relevant refinement of the plasma membrane annotation. Supporting Evidence: PMID:15210697 Anti-Duox antibody staining resulted in prominent apical staining in hTE but no significant staining in Calu-3. PMID:39126279 DUOX1 and DUOX2 are correctly sorted to the apical membrane via the membrane-spanning DUOX maturation proteins DUOXA1 and DUOXA2, respectively, when co-expressed in MDCK epithelial cells PMID:39126279 Impairment of N-glycosylation of DUOXA1 results in mistargeting of DUOX1 to the basolateral membrane. |
| GO:0016324 apical plasma membrane | IDA PMID:39126279 The NADPH oxidases DUOX1 and DUOX2 are sorted to the apical ... | ACCEPT | Summary: In polarized epithelia DUOX1 is delivered to the apical plasma membrane, where it releases H2O2 into the lumen or airway surface liquid. Reason: Core location. Apical staining is seen in primary human tracheal epithelium, and in MDCK cells DUOX1 is sorted apically via N-glycosylated DUOXA1, with mistargeting to the basolateral membrane when that glycosylation is lost. This is the specific, functionally relevant refinement of the plasma membrane annotation. Supporting Evidence: PMID:15210697 Anti-Duox antibody staining resulted in prominent apical staining in hTE but no significant staining in Calu-3. PMID:39126279 DUOX1 and DUOX2 are correctly sorted to the apical membrane via the membrane-spanning DUOX maturation proteins DUOXA1 and DUOXA2, respectively, when co-expressed in MDCK epithelial cells PMID:39126279 Impairment of N-glycosylation of DUOXA1 results in mistargeting of DUOX1 to the basolateral membrane. |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: In polarized epithelia DUOX1 is delivered to the apical plasma membrane, where it releases H2O2 into the lumen or airway surface liquid. Reason: Core location. Apical staining is seen in primary human tracheal epithelium, and in MDCK cells DUOX1 is sorted apically via N-glycosylated DUOXA1, with mistargeting to the basolateral membrane when that glycosylation is lost. This is the specific, functionally relevant refinement of the plasma membrane annotation. Supporting Evidence: PMID:15210697 Anti-Duox antibody staining resulted in prominent apical staining in hTE but no significant staining in Calu-3. PMID:39126279 DUOX1 and DUOX2 are correctly sorted to the apical membrane via the membrane-spanning DUOX maturation proteins DUOXA1 and DUOXA2, respectively, when co-expressed in MDCK epithelial cells PMID:39126279 Impairment of N-glycosylation of DUOXA1 results in mistargeting of DUOX1 to the basolateral membrane. |
| GO:0016324 apical plasma membrane | NAS PMID:10806195 Cloning of two human thyroid cDNAs encoding new members of t... | ACCEPT | Summary: In polarized epithelia DUOX1 is delivered to the apical plasma membrane, where it releases H2O2 into the lumen or airway surface liquid. Reason: Core location. Apical staining is seen in primary human tracheal epithelium, and in MDCK cells DUOX1 is sorted apically via N-glycosylated DUOXA1, with mistargeting to the basolateral membrane when that glycosylation is lost. This is the specific, functionally relevant refinement of the plasma membrane annotation. Supporting Evidence: PMID:15210697 Anti-Duox antibody staining resulted in prominent apical staining in hTE but no significant staining in Calu-3. PMID:39126279 DUOX1 and DUOX2 are correctly sorted to the apical membrane via the membrane-spanning DUOX maturation proteins DUOXA1 and DUOXA2, respectively, when co-expressed in MDCK epithelial cells PMID:39126279 Impairment of N-glycosylation of DUOXA1 results in mistargeting of DUOX1 to the basolateral membrane. |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: Correct but uninformative: the InterPro signatures establish a flavocytochrome oxidoreductase, and the reaction DUOX1 catalyses is known. Reason: The supported specific term is NAD(P)H oxidase H2O2-forming activity, which the gene already carries with experimental and phylogenetic evidence and which is a descendant of GO:0016491. Proposed replacements: NAD(P)H oxidase H2O2-forming activity Supporting Evidence: PMID:15972824 The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca2+-dependent H2O2-generating activity. PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay |
| GO:0019221 cytokine-mediated signaling pathway | IDA PMID:16111680 Differential regulation of dual NADPH oxidases/peroxidases, ... | MODIFY | Summary: The experiment behind this row measured induction of DUOX1 transcript by the Th2 cytokines IL-4 and IL-13. That makes DUOX1 a target of cytokine signaling, not a component of the signaling pathway. Reason: A gene whose expression rises on cytokine treatment responds to the cytokine; it does not thereby transduce the receptor-proximal pathway, and no step of IL-4/IL-13 signal transduction is executed by DUOX1. The honest term is the parent-level cellular response to cytokine stimulus, which the gene already carries from an independent source. This is a deliberate generalization, not a refinement. Proposed replacements: cellular response to cytokine stimulus Supporting Evidence: PMID:16111680 we determined that Duox1 expression was increased several-fold by treatment with the Th2 cytokines IL-4 and IL-13 |
| GO:0020037 heme binding | IDA PMID:33420071 Structures of human dual oxidase 1 complex in low-calcium an... | ACCEPT | Summary: DUOX1 binds two hemes in its transmembrane domain; these carry electrons across the membrane to oxygen. Reason: Core cofactor binding, resolved in the cryo-EM structure of the human complex, where the transmembrane layer harbors the heme-binding sites that form the electron transfer pathway. This is independent of, and not contradicted by, the NOT peroxidase annotation, which concerns the N-terminal peroxidase-homology domain and the heme it does not bind. Supporting Evidence: PMID:33420071 The transmembrane layer is formed by 24 transmembrane helices and harbors the heme-binding sites that provide the electron transfer pathway across the membrane PMID:33420071 key residues for heme binding, such as the heme ligand histidine, are missing in the PHD of hDUOX1 |
| GO:0020037 heme binding | IEA GO_REF:0000120 | ACCEPT | Summary: DUOX1 binds two hemes in its transmembrane domain; these carry electrons across the membrane to oxygen. Reason: Core cofactor binding, resolved in the cryo-EM structure of the human complex, where the transmembrane layer harbors the heme-binding sites that form the electron transfer pathway. This is independent of, and not contradicted by, the NOT peroxidase annotation, which concerns the N-terminal peroxidase-homology domain and the heme it does not bind. Supporting Evidence: PMID:33420071 The transmembrane layer is formed by 24 transmembrane helices and harbors the heme-binding sites that provide the electron transfer pathway across the membrane PMID:33420071 key residues for heme binding, such as the heme ligand histidine, are missing in the PHD of hDUOX1 |
| GO:0020037 heme binding | ISS GO_REF:0000024 | ACCEPT | Summary: DUOX1 binds two hemes in its transmembrane domain; these carry electrons across the membrane to oxygen. Reason: Core cofactor binding, resolved in the cryo-EM structure of the human complex, where the transmembrane layer harbors the heme-binding sites that form the electron transfer pathway. This is independent of, and not contradicted by, the NOT peroxidase annotation, which concerns the N-terminal peroxidase-homology domain and the heme it does not bind. Supporting Evidence: PMID:33420071 The transmembrane layer is formed by 24 transmembrane helices and harbors the heme-binding sites that provide the electron transfer pathway across the membrane PMID:33420071 key residues for heme binding, such as the heme ligand histidine, are missing in the PHD of hDUOX1 |
| GO:0031252 cell leading edge | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Functional DUOX1 accumulates at the leading edge of migrating airway epithelial cells, where its H2O2 output supports motility. Reason: A genuine but context-specific location, secondary to the apical plasma membrane pool that accounts for the gene's main physiological role. The IGI row with a DUOXA1 isoform and the automatic row make the same claim and are kept together. Supporting Evidence: PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. PMID:19339556 DuoxA subunits are responsible for targeting functional oxidases to distinct cellular compartments in lung epithelial cells |
| GO:0031252 cell leading edge | IGI PMID:19339556 Heterodimerization controls localization of Duox-DuoxA NADPH... | KEEP AS NON CORE | Summary: Functional DUOX1 accumulates at the leading edge of migrating airway epithelial cells, where its H2O2 output supports motility. Reason: A genuine but context-specific location, secondary to the apical plasma membrane pool that accounts for the gene's main physiological role. The IGI row with a DUOXA1 isoform and the automatic row make the same claim and are kept together. Supporting Evidence: PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. PMID:19339556 DuoxA subunits are responsible for targeting functional oxidases to distinct cellular compartments in lung epithelial cells |
| GO:0032757 positive regulation of interleukin-8 production | IMP PMID:19386603 ATP-mediated activation of the NADPH oxidase DUOX1 mediates ... | KEEP AS NON CORE | Summary: ATP-activated DUOX1 is required for IL-8/CXCL8 release by airway epithelium in response to bacterial stimuli, acting through redox-dependent EGFR/ERK signaling and ADAM17 activation. Reason: DUOX1 does work here: the H2O2 it produces is the signal that drives the pathway, so this is more than a downstream phenotype. It is kept as non-core because it is one of several signaling consequences of the same oxidase activity rather than an additional function of the protein. Supporting Evidence: PMID:19386603 this study demonstrates that airway epithelial IL-8 production in response to several bacterial stimuli involves ATP release and DUOX1 activation PMID:19386603 ATP-mediated DUOX1 activation resulted in the activation of ERK1/2 and NF-kappaB pathways |
| GO:0042335 cuticle development | IMP PMID:11514595 Tyrosine cross-linking of extracellular matrix is catalyzed ... | REMOVE | Summary: The phenotype behind this IMP is nematode: RNA interference against Ce-Duox1, which is expressed in hypodermal cells underlying the larval cuticle, abolished di- and trityrosine cross-links and disrupted the cuticle. The paper's human experiments are different ones, on the expressed peroxidase domain in vitro, and humans have no cuticle for DUOX1 to build. Reason: This is a cross-species transfer of a C. elegans loss-of-function phenotype onto the human protein, not a human experiment, and the cross-linking chemistry it depends on is lineage-specific. The nematode protein (bli-3, UniProtKB:O61213) sits in PANTHER subfamily PTHR11972:SF175, not in SF75 with human, mouse, rat, dog and pig DUOX1, and its peroxidase-homology domain binds heme covalently and has peroxidase activity whereas the human domain does neither. Both the phylogenetic placement and the biochemistry block the transfer, so the annotation should not stand on the human gene. The underlying nematode finding is not disputed and belongs on bli-3. Supporting Evidence: PMID:11514595 Ce-Duox1 is expressed in hypodermal cells underlying the cuticle of larval animals. PMID:11514595 To investigate function, RNA interference (RNAi) was carried out in C. elegans. PMID:11514595 Thus, Ce-Duox catalyzes the cross-linking of tyrosine residues involved in the stabilization of cuticular extracellular matrix. PMID:19460756 In contrast, CeDUOX1(1-589) binds heme covalently, exhibits a modest peroxidase activity, but does not oxidize bromide ion. PMID:19460756 the isolated hDUOX1(1-593) does not bind heme and has no intrinsic peroxidase activity |
| GO:0042554 superoxide anion generation | IBA GO_REF:0000033 | MODIFY | Summary: DUOX1 generates hydrogen peroxide; superoxide is the product of the NOX branch of the family, and is seen from DUOX only as leakage from immature or mispaired complexes. Reason: The IBA comes from PTN000239643, the deep NOX/DUOX node seeded by NOX1, NOX2, NOX4, NOX5 and rodent and amoebal homologues, and the NAS row rests on the 2000 cloning paper's observation that the ThOX polypeptides are related to gp91phox, which is sequence similarity rather than a measured product. Direct measurement shows the mature thyroid oxidase releases H2O2 rather than superoxide, with superoxide only from the partially glycosylated ER form, and DUOXA1's C-terminus directs DUOX1 to H2O2. The corresponding true process term for this protein is hydrogen peroxide biosynthetic process, which the gene already carries with IDA support. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000239643 · deep NOX/DUOX ancestral node carrying the IBD SUPPORTS SOURCE BUT NOT TARGET Node seeded by NOX-branch members (NOX1, CYBB/NOX2, NOX4, NOX5 and rodent and amoebal homologues); superoxide output is a property of that branch, not of the DUOX clade below it. PANTHER:PTN000944147 · DUOX-specific node carrying the H2O2-forming IBD SUPPORTS TRANSFER Seeds include UniProtKB:Q9NRD9 itself together with DUOX2 and the fly and nematode Duox proteins; PAINT placed NAD(P)H oxidase H2O2-forming activity here, which is the term this row should carry. UniProtKB:P04839 · CYBB/NOX2 (human) SUPPORTS SOURCE BUT NOT TARGET Experimentally a superoxide generator; the seed is sound for the node and wrong for DUOX1. Proposed replacements: hydrogen peroxide biosynthetic process Supporting Evidence: PMID:15972824 it was shown that mature thyroid NADPH oxidase does not release O2*- but H2O2 PMID:15972824 the partially glycosylated form of Duox2, located in the endoplasmic reticulum, generates superoxide in a calcium-dependent manner PMID:10806195 The encoded polypeptides display 83% sequence similarity and are clearly related to gp91(Phox) PMID:22814254 We have shown that the COOH-terminal end of DUOXA1 is responsible for DUOX1-dependent H(2)O(2) generation. |
| GO:0042554 superoxide anion generation | NAS PMID:10806195 Cloning of two human thyroid cDNAs encoding new members of t... | MODIFY | Summary: DUOX1 generates hydrogen peroxide; superoxide is the product of the NOX branch of the family, and is seen from DUOX only as leakage from immature or mispaired complexes. Reason: The IBA comes from PTN000239643, the deep NOX/DUOX node seeded by NOX1, NOX2, NOX4, NOX5 and rodent and amoebal homologues, and the NAS row rests on the 2000 cloning paper's observation that the ThOX polypeptides are related to gp91phox, which is sequence similarity rather than a measured product. Direct measurement shows the mature thyroid oxidase releases H2O2 rather than superoxide, with superoxide only from the partially glycosylated ER form, and DUOXA1's C-terminus directs DUOX1 to H2O2. The corresponding true process term for this protein is hydrogen peroxide biosynthetic process, which the gene already carries with IDA support. Proposed replacements: hydrogen peroxide biosynthetic process Supporting Evidence: PMID:15972824 it was shown that mature thyroid NADPH oxidase does not release O2*- but H2O2 PMID:15972824 the partially glycosylated form of Duox2, located in the endoplasmic reticulum, generates superoxide in a calcium-dependent manner PMID:10806195 The encoded polypeptides display 83% sequence similarity and are clearly related to gp91(Phox) PMID:22814254 We have shown that the COOH-terminal end of DUOXA1 is responsible for DUOX1-dependent H(2)O(2) generation. |
| GO:0043020 NADPH oxidase complex | IBA GO_REF:0000033 | ACCEPT | Summary: DUOX1 is a subunit of a membrane NADPH oxidase complex with DUOXA1, resolved by cryo-EM as a heterotetramer of two DUOX1-DUOXA1 heterodimers. Reason: Core. Complex membership is established structurally for the human proteins and is the form in which the enzyme is active; the IBA at PTN000239643 makes the same claim at family level with this protein among its seeds. Supporting Evidence: file:human/DUOX1/DUOX1-uniprot.txt SUBUNIT: Heterotetramer with DUOXA1 consisting of 2 DUOX1-DUOXA1 PMID:33420071 the functional DUOX protein has an additional large N-terminal extracellular peroxidase homology domain (PHD) and a long intracellular loop 0 containing two EF-hand domains, and it requires an auxiliary DUOXA protein for proper function PMID:19339556 Characterization of novel DuoxA1 isoforms and mispaired Duox-DuoxA complexes revealed that heterodimerization is a prerequisite for reactive oxygen species production. |
| GO:0043020 NADPH oxidase complex | IEA GO_REF:0000120 | ACCEPT | Summary: DUOX1 is a subunit of a membrane NADPH oxidase complex with DUOXA1, resolved by cryo-EM as a heterotetramer of two DUOX1-DUOXA1 heterodimers. Reason: Core. Complex membership is established structurally for the human proteins and is the form in which the enzyme is active; the IBA at PTN000239643 makes the same claim at family level with this protein among its seeds. Supporting Evidence: file:human/DUOX1/DUOX1-uniprot.txt SUBUNIT: Heterotetramer with DUOXA1 consisting of 2 DUOX1-DUOXA1 PMID:33420071 the functional DUOX protein has an additional large N-terminal extracellular peroxidase homology domain (PHD) and a long intracellular loop 0 containing two EF-hand domains, and it requires an auxiliary DUOXA protein for proper function PMID:19339556 Characterization of novel DuoxA1 isoforms and mispaired Duox-DuoxA complexes revealed that heterodimerization is a prerequisite for reactive oxygen species production. |
| GO:0043020 NADPH oxidase complex | IPI PMID:33420071 Structures of human dual oxidase 1 complex in low-calcium an... | ACCEPT | Summary: DUOX1 is a subunit of a membrane NADPH oxidase complex with DUOXA1, resolved by cryo-EM as a heterotetramer of two DUOX1-DUOXA1 heterodimers. Reason: Core. Complex membership is established structurally for the human proteins and is the form in which the enzyme is active; the IBA at PTN000239643 makes the same claim at family level with this protein among its seeds. Supporting Evidence: file:human/DUOX1/DUOX1-uniprot.txt SUBUNIT: Heterotetramer with DUOXA1 consisting of 2 DUOX1-DUOXA1 PMID:33420071 the functional DUOX protein has an additional large N-terminal extracellular peroxidase homology domain (PHD) and a long intracellular loop 0 containing two EF-hand domains, and it requires an auxiliary DUOXA protein for proper function PMID:19339556 Characterization of novel DuoxA1 isoforms and mispaired Duox-DuoxA complexes revealed that heterodimerization is a prerequisite for reactive oxygen species production. |
| GO:0046982 protein heterodimerization activity | IEA GO_REF:0000107 | ACCEPT | Summary: DUOX1 forms an obligate heterodimer with its maturation factor DUOXA1; heterodimerization is required for maturation, surface delivery and ROS production. Reason: Core, and the informative replacement chosen for the generic protein-binding rows in this review. The mouse-based ISS/IEA inference is confirmed directly in human cells and in the human complex structure, so no cross-species caveat is needed. Supporting Evidence: PMID:19339556 Duox proteins form functional heterodimers with their respective DuoxA subunits, in close analogy to the phagocyte NADPH oxidase. PMID:19339556 Characterization of novel DuoxA1 isoforms and mispaired Duox-DuoxA complexes revealed that heterodimerization is a prerequisite for reactive oxygen species production. file:human/DUOX1/DUOX1-uniprot.txt SUBUNIT: Heterotetramer with DUOXA1 consisting of 2 DUOX1-DUOXA1 |
| GO:0046982 protein heterodimerization activity | ISS GO_REF:0000024 | ACCEPT | Summary: DUOX1 forms an obligate heterodimer with its maturation factor DUOXA1; heterodimerization is required for maturation, surface delivery and ROS production. Reason: Core, and the informative replacement chosen for the generic protein-binding rows in this review. The mouse-based ISS/IEA inference is confirmed directly in human cells and in the human complex structure, so no cross-species caveat is needed. Supporting Evidence: PMID:19339556 Duox proteins form functional heterodimers with their respective DuoxA subunits, in close analogy to the phagocyte NADPH oxidase. PMID:19339556 Characterization of novel DuoxA1 isoforms and mispaired Duox-DuoxA complexes revealed that heterodimerization is a prerequisite for reactive oxygen species production. file:human/DUOX1/DUOX1-uniprot.txt SUBUNIT: Heterotetramer with DUOXA1 consisting of 2 DUOX1-DUOXA1 |
| GO:0050661 NADP binding | NAS PMID:10806195 Cloning of two human thyroid cDNAs encoding new members of t... | MODIFY | Summary: Correct but less specific than the evidence supports: the dehydrogenase domain binds NADPH, the reduced substrate, which is resolved in the structure. Reason: NADPH binding is a descendant of NADP binding and is already annotated to this gene from the cryo-EM structure, so the specific term is the one to keep. The NAS row is not wrong, only general. Proposed replacements: NADPH binding Supporting Evidence: PMID:33420071 The DH domain binds intracellular substrate NADPH and cofactor FAD PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay |
| GO:0050665 hydrogen peroxide biosynthetic process | IDA PMID:33420071 Structures of human dual oxidase 1 complex in low-calcium an... | ACCEPT | Summary: Hydrogen peroxide biosynthesis is the process DUOX1 executes; the reconstituted DUOX1-DUOXA1 complex produces H2O2 in a calcium- and NADPH-dependent manner. Reason: Core process term, matching the accepted molecular function. The genetic-interaction rows with DUOXA1 reflect the requirement for the maturation factor rather than a different claim. Supporting Evidence: PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:22814254 We have shown that the COOH-terminal end of DUOXA1 is responsible for DUOX1-dependent H(2)O(2) generation. PMID:15972824 The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca2+-dependent H2O2-generating activity. |
| GO:0050665 hydrogen peroxide biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Hydrogen peroxide biosynthesis is the process DUOX1 executes; the reconstituted DUOX1-DUOXA1 complex produces H2O2 in a calcium- and NADPH-dependent manner. Reason: Core process term, matching the accepted molecular function. The genetic-interaction rows with DUOXA1 reflect the requirement for the maturation factor rather than a different claim. Supporting Evidence: PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:22814254 We have shown that the COOH-terminal end of DUOXA1 is responsible for DUOX1-dependent H(2)O(2) generation. PMID:15972824 The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca2+-dependent H2O2-generating activity. |
| GO:0050665 hydrogen peroxide biosynthetic process | IGI PMID:19339556 Heterodimerization controls localization of Duox-DuoxA NADPH... | ACCEPT | Summary: Hydrogen peroxide biosynthesis is the process DUOX1 executes; the reconstituted DUOX1-DUOXA1 complex produces H2O2 in a calcium- and NADPH-dependent manner. Reason: Core process term, matching the accepted molecular function. The genetic-interaction rows with DUOXA1 reflect the requirement for the maturation factor rather than a different claim. Supporting Evidence: PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:22814254 We have shown that the COOH-terminal end of DUOXA1 is responsible for DUOX1-dependent H(2)O(2) generation. PMID:15972824 The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca2+-dependent H2O2-generating activity. |
| GO:0050665 hydrogen peroxide biosynthetic process | IGI PMID:22814254 The type of DUOX-dependent ROS production is dictated by def... | ACCEPT | Summary: Hydrogen peroxide biosynthesis is the process DUOX1 executes; the reconstituted DUOX1-DUOXA1 complex produces H2O2 in a calcium- and NADPH-dependent manner. Reason: Core process term, matching the accepted molecular function. The genetic-interaction rows with DUOXA1 reflect the requirement for the maturation factor rather than a different claim. Supporting Evidence: PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:22814254 We have shown that the COOH-terminal end of DUOXA1 is responsible for DUOX1-dependent H(2)O(2) generation. PMID:15972824 The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca2+-dependent H2O2-generating activity. |
| GO:0050665 hydrogen peroxide biosynthetic process | NAS PMID:10806195 Cloning of two human thyroid cDNAs encoding new members of t... | ACCEPT | Summary: Hydrogen peroxide biosynthesis is the process DUOX1 executes; the reconstituted DUOX1-DUOXA1 complex produces H2O2 in a calcium- and NADPH-dependent manner. Reason: Core process term, matching the accepted molecular function. The genetic-interaction rows with DUOXA1 reflect the requirement for the maturation factor rather than a different claim. Supporting Evidence: PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:22814254 We have shown that the COOH-terminal end of DUOXA1 is responsible for DUOX1-dependent H(2)O(2) generation. PMID:15972824 The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca2+-dependent H2O2-generating activity. |
| GO:0050665 hydrogen peroxide biosynthetic process | TAS Reactome:R-HSA-5693681 | ACCEPT | Summary: Hydrogen peroxide biosynthesis is the process DUOX1 executes; the reconstituted DUOX1-DUOXA1 complex produces H2O2 in a calcium- and NADPH-dependent manner. Reason: Core process term, matching the accepted molecular function. The genetic-interaction rows with DUOXA1 reflect the requirement for the maturation factor rather than a different claim. Supporting Evidence: PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay PMID:22814254 We have shown that the COOH-terminal end of DUOXA1 is responsible for DUOX1-dependent H(2)O(2) generation. PMID:15972824 The particulate fractions of these cells stably or transiently transfected with human or porcine DUOX cDNA demonstrate a functional NADPH/Ca2+-dependent H2O2-generating activity. |
| GO:0051591 response to cAMP | IDA PMID:15062544 Structural and functional characterization of the two human ... | KEEP AS NON CORE | Summary: DUOX1 protein levels rise on forskolin treatment and on thyrotropin stimulation, so the gene responds to raised cAMP; this is regulation of its expression, not part of its molecular function. Reason: Kept as non-core with an explicit caveat about the IDA's source: the promoter study cited by that row reports that the two human ThOX promoters are not positively controlled by cAMP, so it is a weak basis for the term. The curated UniProt induction statement (forskolin at protein level, and thyrotropin) is what supports it, and the ISS row propagates the same claim from the paralog DUOX2. All three rows are treated alike because they assert one claim. Supporting Evidence: file:human/DUOX1/DUOX1-uniprot.txt INDUCTION: By forskolin (at protein level). PMID:15062544 functional studies show that both hThOX promoters are not positively controlled by cAMP |
| GO:0051591 response to cAMP | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: DUOX1 protein levels rise on forskolin treatment and on thyrotropin stimulation, so the gene responds to raised cAMP; this is regulation of its expression, not part of its molecular function. Reason: Kept as non-core with an explicit caveat about the IDA's source: the promoter study cited by that row reports that the two human ThOX promoters are not positively controlled by cAMP, so it is a weak basis for the term. The curated UniProt induction statement (forskolin at protein level, and thyrotropin) is what supports it, and the ISS row propagates the same claim from the paralog DUOX2. All three rows are treated alike because they assert one claim. Supporting Evidence: file:human/DUOX1/DUOX1-uniprot.txt INDUCTION: By forskolin (at protein level). PMID:15062544 functional studies show that both hThOX promoters are not positively controlled by cAMP |
| GO:0051591 response to cAMP | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: DUOX1 protein levels rise on forskolin treatment and on thyrotropin stimulation, so the gene responds to raised cAMP; this is regulation of its expression, not part of its molecular function. Reason: Kept as non-core with an explicit caveat about the IDA's source: the promoter study cited by that row reports that the two human ThOX promoters are not positively controlled by cAMP, so it is a weak basis for the term. The curated UniProt induction statement (forskolin at protein level, and thyrotropin) is what supports it, and the ISS row propagates the same claim from the paralog DUOX2. All three rows are treated alike because they assert one claim. Supporting Evidence: file:human/DUOX1/DUOX1-uniprot.txt INDUCTION: By forskolin (at protein level). PMID:15062544 functional studies show that both hThOX promoters are not positively controlled by cAMP |
| GO:0070402 NADPH binding | IDA PMID:33420071 Structures of human dual oxidase 1 complex in low-calcium an... | ACCEPT | Summary: The cytosolic dehydrogenase domain of DUOX1 binds NADPH, the electron donor for the oxidase reaction. Reason: Core cofactor/substrate binding, resolved in the human complex structure and consistent with the NADPH dependence of the reconstituted activity. Supporting Evidence: PMID:33420071 The DH domain binds intracellular substrate NADPH and cofactor FAD PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay |
| GO:0070402 NADPH binding | IEA GO_REF:0000107 | ACCEPT | Summary: The cytosolic dehydrogenase domain of DUOX1 binds NADPH, the electron donor for the oxidase reaction. Reason: Core cofactor/substrate binding, resolved in the human complex structure and consistent with the NADPH dependence of the reconstituted activity. Supporting Evidence: PMID:33420071 The DH domain binds intracellular substrate NADPH and cofactor FAD PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay |
| GO:0070402 NADPH binding | ISS GO_REF:0000024 | ACCEPT | Summary: The cytosolic dehydrogenase domain of DUOX1 binds NADPH, the electron donor for the oxidase reaction. Reason: Core cofactor/substrate binding, resolved in the human complex structure and consistent with the NADPH dependence of the reconstituted activity. Supporting Evidence: PMID:33420071 The DH domain binds intracellular substrate NADPH and cofactor FAD PMID:33420071 we found the co-expression of DUOX1 and DUOXA1 resulted in cell membranes that showed robust calcium-activated, NADPH-dependent hydrogen peroxide production detected by the Amplex Red assay |
| GO:0071345 cellular response to cytokine stimulus | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: DUOX1 expression in airway epithelium is induced several-fold by the Th2 cytokines IL-4 and IL-13. Reason: A real but regulatory relationship: DUOX1 is a target of cytokine signaling rather than a transducer of it. This is also the replacement term proposed for the cytokine-mediated signaling pathway row in this review, so the two are consistent. Supporting Evidence: PMID:16111680 we determined that Duox1 expression was increased several-fold by treatment with the Th2 cytokines IL-4 and IL-13 |
| GO:0071949 FAD binding | IDA PMID:33420071 Structures of human dual oxidase 1 complex in low-calcium an... | ACCEPT | Summary: The dehydrogenase domain binds FAD, the flavin that relays electrons from NADPH to the transmembrane hemes. Reason: Core cofactor binding, resolved in the structure of the human DUOX1-DUOXA1 complex. Supporting Evidence: PMID:33420071 The DH domain binds intracellular substrate NADPH and cofactor FAD PMID:33420071 The transmembrane layer is formed by 24 transmembrane helices and harbors the heme-binding sites that provide the electron transfer pathway across the membrane |
| GO:0071949 FAD binding | IEA GO_REF:0000107 | ACCEPT | Summary: The dehydrogenase domain binds FAD, the flavin that relays electrons from NADPH to the transmembrane hemes. Reason: Core cofactor binding, resolved in the structure of the human DUOX1-DUOXA1 complex. Supporting Evidence: PMID:33420071 The DH domain binds intracellular substrate NADPH and cofactor FAD PMID:33420071 The transmembrane layer is formed by 24 transmembrane helices and harbors the heme-binding sites that provide the electron transfer pathway across the membrane |
| GO:0071949 FAD binding | ISS GO_REF:0000024 | ACCEPT | Summary: The dehydrogenase domain binds FAD, the flavin that relays electrons from NADPH to the transmembrane hemes. Reason: Core cofactor binding, resolved in the structure of the human DUOX1-DUOXA1 complex. Supporting Evidence: PMID:33420071 The DH domain binds intracellular substrate NADPH and cofactor FAD PMID:33420071 The transmembrane layer is formed by 24 transmembrane helices and harbors the heme-binding sites that provide the electron transfer pathway across the membrane |
| GO:0090303 positive regulation of wound healing | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Functional DUOX1 at the leading edge of migrating airway epithelial cells augments motility and wound healing. Reason: A redox-signaling consequence of the oxidase activity in a specific cellular context, kept as non-core rather than treated as an additional function of the protein. Supporting Evidence: PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0090303 positive regulation of wound healing | IGI PMID:19339556 Heterodimerization controls localization of Duox-DuoxA NADPH... | KEEP AS NON CORE | Summary: Functional DUOX1 at the leading edge of migrating airway epithelial cells augments motility and wound healing. Reason: A redox-signaling consequence of the oxidase activity in a specific cellular context, kept as non-core rather than treated as an additional function of the protein. Supporting Evidence: PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0140374 antiviral innate immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: DUOX1-derived H2O2 is the substrate from which lactoperoxidase makes hypothiocyanite, which inactivates influenza virus; Duox1-null mice show impaired viral clearance and worse disease. Reason: DUOX1 performs the H2O2-forming step of this defense mechanism, so this is participation rather than a downstream phenotype, but it is one of several physiological uses of the same activity and so is kept as non-core. The in vivo evidence is murine and the mechanistic work is in primary human tracheobronchial cells, which is why the human and Ensembl-projected rows agree. Supporting Evidence: PMID:34168077 Here, we show that Duox1 promotes antiviral innate immunity in vivo. PMID:34168077 Upon influenza airway challenge, Duox1-/- mice have enhanced mortality, morbidity, and impaired lung viral clearance. PMID:34168077 In primary human tracheobronchial epithelial cells, OSCN- is generated by LPO using DUOX1-derived H2O2 and inactivates several influenza strains in vitro. PMID:34168077 Duox1 increases the airway levels of several cytokines |
| GO:0140374 antiviral innate immune response | IMP PMID:34168077 Dual oxidase 1 promotes antiviral innate immunity. | KEEP AS NON CORE | Summary: DUOX1-derived H2O2 is the substrate from which lactoperoxidase makes hypothiocyanite, which inactivates influenza virus; Duox1-null mice show impaired viral clearance and worse disease. Reason: DUOX1 performs the H2O2-forming step of this defense mechanism, so this is participation rather than a downstream phenotype, but it is one of several physiological uses of the same activity and so is kept as non-core. The in vivo evidence is murine and the mechanistic work is in primary human tracheobronchial cells, which is why the human and Ensembl-projected rows agree. Supporting Evidence: PMID:34168077 Here, we show that Duox1 promotes antiviral innate immunity in vivo. PMID:34168077 Upon influenza airway challenge, Duox1-/- mice have enhanced mortality, morbidity, and impaired lung viral clearance. PMID:34168077 In primary human tracheobronchial epithelial cells, OSCN- is generated by LPO using DUOX1-derived H2O2 and inactivates several influenza strains in vitro. PMID:34168077 Duox1 increases the airway levels of several cytokines |
| GO:1900426 positive regulation of defense response to bacterium | IDA PMID:19386603 ATP-mediated activation of the NADPH oxidase DUOX1 mediates ... | KEEP AS NON CORE | Summary: ATP released during bacterial challenge activates DUOX1, and the resulting H2O2 drives the epithelial inflammatory response to those stimuli. Reason: Participation through the oxidase activity, in a defined airway context; non-core relative to the molecular function and the H2O2 biosynthetic process that produce it. Supporting Evidence: PMID:19386603 Activation of the NADPH oxidase homolog dual oxidase 1 (DUOX1) within the airway epithelium represents a key mechanism of innate airway host defense, through enhanced production of H2O2 PMID:19386603 this study demonstrates that airway epithelial IL-8 production in response to several bacterial stimuli involves ATP release and DUOX1 activation |
| GO:2000147 positive regulation of cell motility | IGI PMID:19339556 Heterodimerization controls localization of Duox-DuoxA NADPH... | KEEP AS NON CORE | Summary: DUOX1 at the leading edge augments motility of airway epithelial cells, shown by genetic interaction with its DUOXA1 partner. Reason: Context-specific redox signaling downstream of the same oxidase activity; kept as non-core. Supporting Evidence: PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:2000609 regulation of thyroid hormone generation | NAS PMID:25761904 When an Intramolecular Disulfide Bridge Governs the Interact... | KEEP AS NON CORE | Summary: Because H2O2 supply is the limiting factor for peroxidase-catalysed iodination, the amount of DUOX activity at the apical thyrocyte membrane sets the rate of hormone synthesis. Reason: Retained as non-core alongside the thyroid hormone generation row: both describe the same contribution and DUOX2, not DUOX1, is the thyroid-dominant paralog. The NAS source is a DUOX2/DUOXA2 study, so it carries the family-level claim rather than DUOX1-specific evidence; it is not removed, because the underlying biochemistry applies to both paralogs where DUOX1 is expressed in thyrocytes. Supporting Evidence: PMID:15062544 The limiting factor of this reaction is the supply of hydrogen peroxide. PMID:25761904 As H2O2 generator, it plays a key role in both thyroid hormone biosynthesis and innate immunity. PMID:10806195 Two cDNAs encoding NADPH oxidases and constituting the thyroid H(2)O(2) generating system have been cloned. |
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Download this section (compressed HTML)Q: What is the function of the human DUOX1 peroxidase-homology domain, given that it binds no heme and has no peroxidase activity? Does it instead dock an extracellular peroxidase such as lactoperoxidase so that H2O2 is channelled directly to it?
Q: Should the conflict between PMID:11514595 (peroxidase activity from an E. coli-expressed human Duox peroxidase domain) and PMID:19460756 plus the cryo-EM structure (no heme, no activity) be resolved in GO by keeping the NOT GO:0004601 annotation, as this review recommends, or by recording both? UniProt currently records both in a CAUTION line.
Q: Does GO need a molecular function for the NAADPH-oxidizing, NAADP-forming reaction that UniProt attributes to DUOX1 (Rhea:86235), and is the reaction physiologically relevant for DUOX1 as opposed to DUOX2, which carried the T-cell calcium-microdomain phenotype?
Q: Where DUOX1 and DUOX2 are co-expressed, which peroxidase consumes which oxidase's H2O2? The substrate-channelling question determines whether thyroid hormone generation and lactoperoxidase-dependent defense should be annotated to both paralogs or only to one.
Experiment: Express and purify the isolated human DUOX1 PHD and test binding to lactoperoxidase and thyroid peroxidase by surface plasmon resonance and by pull-down from airway secretions; then delete or swap the PHD in full-length DUOX1 co-expressed with DUOXA1 in polarized MDCK or primary airway cells and measure whether hypothiocyanite production, but not bulk H2O2 output, is lost.
Hypothesis: The human DUOX1 peroxidase-homology domain is a protein-interaction module that recruits extracellular peroxidases rather than a catalytic domain.
Type: binding and reconstitution assay
Experiment: Compare spin-trapping EPR and Amplex Red measurements on purified, peptidisc-reconstituted human DUOX1-DUOXA1 against the immature ER-resident form and against DUOX1 mispaired with DUOXA2, under identical calcium and NADPH conditions, to quantify the superoxide-to-H2O2 ratio for each species.
Hypothesis: DUOX1 releases H2O2 and never superoxide, whereas the superoxide seen in DUOX preparations comes from immature or mispaired complexes.
Type: biochemistry
Experiment: Reconstitute purified DUOX1-DUOXA1 and DUOX2-DUOXA2 with NAADPH and measure NAADP formation by LC-MS as a function of calcium, in parallel with H2O2 output, and test DUOX1-null airway epithelial cells for altered NAADP levels and calcium signalling.
Hypothesis: The NAADPH-oxidizing activity attributed to DUOX enzymes is carried by DUOX1 in cells where DUOX1 is the dominant paralog.
Type: enzymology and cell biology
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: What the extracellular peroxidase-homology domain of human DUOX1 does is unknown. It occupies roughly the first 590 residues, is retained throughout vertebrate DUOX evolution, and yet binds no heme and shows no peroxidase activity in the human protein, while the C. elegans equivalent binds heme covalently and cross-links cuticle tyrosines.
OPEN BIOLOGY MF_DARK
Significance: Without knowing the domain's function it is not possible to say whether human DUOX1 has a second catalytic or ligand-handling activity, or whether the domain is purely structural, holding the complex at the membrane surface or positioning a partner peroxidase such as lactoperoxidase.
Provenance (the field's own admissions):
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