Dual oxidase 1 (Duox1) is a multi-pass transmembrane flavocytochrome that forms an obligate heterodimeric and heterotetrameric complex with the maturation factor Duoxa1 at the apical plasma membrane of epithelial cells to generate extracellular hydrogen peroxide (H2O2). Its cytosolic dehydrogenase domain binds NADPH and FAD and transfers electrons through two transmembrane hemes coordinated within helices S2-S5 (via Phe1097) to reduce extracellular O2 to H2O2 in a calcium-regulated manner mediated by intracellular EF-hand domains. Although Duox1 possesses a large N-terminal extracellular peroxidase-homology domain, cryo-EM structures of the mouse Duox1-Duoxa1 complex demonstrate that this domain lacks heme-coordinating histidines, binds no heme, and has no intrinsic peroxidase activity. Duox1-derived H2O2 serves as the substrate for lactoperoxidase-catalyzed hypothiocyanite synthesis in airway mucosal antiviral and antibacterial innate immunity, supports thyroid peroxidase-mediated thyroid hormone biosynthesis, and acts as a diffusible redox signal in epithelial wound repair, cell motility, and neural stem cell differentiation.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004601 peroxidase activity | ISS NOT GO_REF:0000024 | ACCEPT | Summary: Cryo-EM structures of the mouse DUOX1-DUOXA1 complex directly confirm that the extracellular N-terminal peroxidase-homology domain (PHD) lacks heme-coordinating histidines, binds no heme, and has no intrinsic peroxidase activity. Reason: Keep the NOT annotation. In mouse DUOX1, just as in human DUOX1 (UniProtKB:Q9NRD9), the N-terminal PHD (residues 26-593) adopts a peroxidase-like fold but lacks the histidines required for heme coordination and shows no heme density in high-resolution cryo-EM maps (PMID:32929281). The two catalytic hemes of DUOX1 reside in the transmembrane ferric-reductase domain rather than the PHD. Supporting Evidence: PMID:32929281 Though the PHD of DUOX1 has an overall architecture of peroxidase with an RMSD of 1.3 Γ
when superimposed with the bovine lactoperoxidase (LPO, PDB 5B72) (Extended Data Fig. 2a)21, the facts that no heme density is observed in the cryo-EM map and histidines needed for heme coordination are missing in the putative binding pocket strongly suggest that the PHD domain of DUOX1 lacks heme-dependent peroxidase activity. file:mouse/Duox1/Duox1-uniprot.txt CAUTION: The role of the N-terminal peroxidase-like domain is unclear. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000120 | ACCEPT | Summary: Mouse DUOX1 binds calcium ions both at a structural cation-binding site in its extracellular PHD and via intracellular EF-hand domains that gate NADPH oxidase activity. Reason: Core. Cryo-EM structures of mouse DUOX1-DUOXA1 resolve a bound cation (Ca2+) in the PHD (coordinated by Glu109, Asp170, Asn172, Asp174, and Trp176) and intracellular EF-hand modules (residues 815-930) that mediate calcium-dependent activation of H2O2 production. Supporting Evidence: PMID:32929281 Here I report cryo-EM structures of mouse DUOX1βDUOXA1 complexes in NADPH-free, NADPH-bound and dimer-of-dimer states, providing structural mechanisms underlying DUOX1βDUOXA1 activation and regulation and molecular insights into ROS production. file:mouse/Duox1/Duox1-uniprot.txt ACTIVITY REGULATION: The NADPH oxidase activity is calcium-dependent. |
| GO:0005509 calcium ion binding | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse DUOX1 binds calcium ions both at a structural cation-binding site in its extracellular PHD and via intracellular EF-hand domains that gate NADPH oxidase activity. Reason: Core. Ortholog projection from human DUOX1 (UniProtKB:Q9NRD9) is directly confirmed in mouse DUOX1 by cryo-EM and biochemical characterization. Supporting Evidence: PMID:32929281 Here I report cryo-EM structures of mouse DUOX1βDUOXA1 complexes in NADPH-free, NADPH-bound and dimer-of-dimer states, providing structural mechanisms underlying DUOX1βDUOXA1 activation and regulation and molecular insights into ROS production. file:mouse/Duox1/Duox1-uniprot.txt ACTIVITY REGULATION: The NADPH oxidase activity is calcium-dependent. |
| GO:0005515 protein binding | IPI PMID:20233719 Mammalian numb-interacting protein 1/dual oxidase maturation... | MODIFY | Summary: Physical interaction of mouse DUOX1 with its obligate maturation partner DUOXA1/Nip1 (UniProtKB:Q8VE49); bare protein binding is uninformative and is refined to protein heterodimerization activity. Reason: Under the repository protein-binding policy, bare GO:0005515 is replaced by the specific informative molecular function GO:0046982 (protein heterodimerization activity), which mouse Duox1 already carries from the cryo-EM structure with DUOXA1 (UniProtKB:Q8VE49). Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:20233719 The highest expression of Nip1 was observed in undifferentiated neuronal stem cells and was associated with Duox1-mediated reactive oxygen species ROS production. file:mouse/Duox1/Duox1-uniprot.txt Heterotetramer with DUOXA1 consisting of 2 DUOX1-DUOXA1 heterodimers (PubMed:32929281). |
| GO:0005515 protein binding | IPI PMID:32929281 Structures of mouse DUOX1-DUOXA1 provide mechanistic insight... | MODIFY | Summary: Physical interaction of mouse DUOX1 with its obligate maturation partner DUOXA1 (UniProtKB:Q8VE49) in the cryo-EM structure; refined from bare protein binding to protein heterodimerization activity. Reason: Bare GO:0005515 is replaced by GO:0046982 (protein heterodimerization activity), which is already annotated to mouse Duox1 from the same cryo-EM study (PMID:32929281). Proposed replacements: protein heterodimerization activity Supporting Evidence: PMID:32929281 Here I report cryo-EM structures of mouse DUOX1βDUOXA1 complexes in NADPH-free, NADPH-bound and dimer-of-dimer states, providing structural mechanisms underlying DUOX1βDUOXA1 activation and regulation and molecular insights into ROS production. file:mouse/Duox1/Duox1-uniprot.txt Heterotetramer with DUOXA1 consisting of 2 DUOX1-DUOXA1 heterodimers (PubMed:32929281). |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Endoplasmic reticulum localization reflects biosynthetic folding, disulfide formation, and N-glycosylation of DUOX1 prior to DUOXA1-dependent trafficking to the plasma membrane. Reason: Root organelle term retained as non-core. Immature DUOX1 is folded and N-glycosylated in the ER before pairing with DUOXA1 for cell-surface delivery, whereas mature catalytic H2O2 generation takes place at the plasma membrane. Supporting Evidence: 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 as it promotes an appropriate conformation of the N-terminal region, which is propitious to subsequent covalent interactions with the maturation factor, DUOXA2. |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Endoplasmic reticulum localization reflects biosynthetic folding, disulfide formation, and N-glycosylation of DUOX1 prior to DUOXA1-dependent trafficking to the plasma membrane. Reason: Root organelle term retained as non-core, consistent with the IEA ortholog projection row. Supporting Evidence: 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 as it promotes an appropriate conformation of the N-terminal region, which is propitious to subsequent covalent interactions with the maturation factor, DUOXA2. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The mature mouse DUOX1-DUOXA1 complex localizes to and is active in the plasma membrane, transferring electrons from cytosolic NADPH to extracellular oxygen. Reason: Core cellular location. Mouse Duox1 (MGI:2139422) is itself an experimental seed for PAINT node PTN001735877, and plasma membrane localization is supported in both polarized epithelia (apical membrane) and non-polarized neural stem cells (PMID:20233719; PMID:32929281). Supporting Evidence: PMID:32929281 Here I report cryo-EM structures of mouse DUOX1βDUOXA1 complexes in NADPH-free, NADPH-bound and dimer-of-dimer states, providing structural mechanisms underlying DUOX1βDUOXA1 activation and regulation and molecular insights into ROS production. PMID:20233719 The highest expression of Nip1 was observed in undifferentiated neuronal stem cells and was associated with Duox1-mediated reactive oxygen species ROS production. |
| GO:0005886 plasma membrane | IDA PMID:20233719 Mammalian numb-interacting protein 1/dual oxidase maturation... | ACCEPT | Summary: Direct experimental localization of mouse Duox1 to the plasma membrane in differentiating neural stem cells. Reason: Core cellular location, directly assayed in mouse cells (PMID:20233719) and structurally characterized (PMID:32929281). Supporting Evidence: PMID:20233719 The highest expression of Nip1 was observed in undifferentiated neuronal stem cells and was associated with Duox1-mediated reactive oxygen species ROS production. file:mouse/Duox1/Duox1-uniprot.txt SUBCELLULAR LOCATION: Apical cell membrane {ECO:0000250|UniProtKB:Q9NRD9}; Multi-pass membrane protein {ECO:0000269|PubMed:32929281}. |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: The mature mouse DUOX1-DUOXA1 complex localizes to and is active in the plasma membrane. Reason: Core cellular location, consistent with the IDA and IBA rows. Supporting Evidence: file:mouse/Duox1/Duox1-uniprot.txt SUBCELLULAR LOCATION: Apical cell membrane {ECO:0000250|UniProtKB:Q9NRD9}; Multi-pass membrane protein {ECO:0000269|PubMed:32929281}. |
| GO:0005886 plasma membrane | ISO GO_REF:0000119 | ACCEPT | Summary: The mature mouse DUOX1-DUOXA1 complex localizes to and is active in the plasma membrane. Reason: Core cellular location, consistent with the IDA and IBA rows. Supporting Evidence: file:mouse/Duox1/Duox1-uniprot.txt SUBCELLULAR LOCATION: Apical cell membrane {ECO:0000250|UniProtKB:Q9NRD9}; Multi-pass membrane protein {ECO:0000269|PubMed:32929281}. |
| GO:0006590 thyroid hormone generation | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: DUOX1 supplies extracellular H2O2 used by thyroid peroxidase for thyroglobulin iodination, although DUOX2 is the dominant thyroid paralog. Reason: Kept as non-core matching human DUOX1. While DUOX1 catalyses the H2O2-forming half-reaction in thyrocytes, DUOX2 is the primary physiological H2O2 source for thyroid hormone synthesis, whereas DUOX1 is predominantly an airway mucosal oxidase. Supporting Evidence: PMID:25761904 As H2O2 generator, it plays a key role in both thyroid hormone biosynthesis and innate immunity. file:mouse/Duox1/Duox1-uniprot.txt Plays a role in thyroid hormone synthesis (By similarity). |
| GO:0006952 defense response | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: DUOX1-derived H2O2 supports mucosal innate defense against viral and bacterial pathogens, a role conserved across the NOX/DUOX family. Reason: True and broadly supported across the NOX/DUOX clade at PAINT node PTN000239643 (with mouse Duox1 MGI:2139422 among its seeds), but kept as non-core because more specific defense terms (GO:0140374 antiviral innate immune response; GO:1900426 positive regulation of defense response to bacterium) capture its physiological contributions. 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. |
| GO:0006979 response to oxidative stress | IEA GO_REF:0000002 | REMOVE | Summary: Unwarranted InterPro2GO mapping from the haem peroxidase domain superfamily signature (IPR010255); mouse DUOX1 PHD lacks heme and peroxidase activity, and DUOX1 generates H2O2 rather than responding to oxidative stress. Reason: In mouse DUOX1, cryo-EM demonstrates that the N-terminal peroxidase-homology domain matched by IPR010255 lacks heme-coordinating histidines and binds no heme (PMID:32929281). Moreover, DUOX1 is an oxidant-producing NADPH oxidase rather than an enzyme that detoxifies or responds to oxidative stress. Supporting Evidence: PMID:32929281 Though the PHD of DUOX1 has an overall architecture of peroxidase with an RMSD of 1.3 Γ
when superimposed with the bovine lactoperoxidase (LPO, PDB 5B72) (Extended Data Fig. 2a)21, the facts that no heme density is observed in the cryo-EM map and histidines needed for heme coordination are missing in the putative binding pocket strongly suggest that the PHD domain of DUOX1 lacks heme-dependent peroxidase activity. |
| GO:0009986 cell surface | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mature DUOX1-DUOXA1 complexes are delivered to the cell surface, with the extracellular PHD exposed on the outer face of the plasma membrane. Reason: True but coarse relative to the accepted plasma membrane (GO:0005886) and apical plasma membrane (GO:0016324) annotations; kept as non-core in agreement with the human DUOX1 review. Supporting Evidence: file:mouse/Duox1/Duox1-uniprot.txt SUBCELLULAR LOCATION: Apical cell membrane {ECO:0000250|UniProtKB:Q9NRD9}; Multi-pass membrane protein {ECO:0000269|PubMed:32929281}. |
| GO:0009986 cell surface | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Mature DUOX1-DUOXA1 complexes are delivered to the cell surface, with the extracellular PHD exposed on the outer face of the plasma membrane. Reason: True but coarse relative to plasma membrane and apical plasma membrane; kept as non-core in agreement with the IEA row. Supporting Evidence: file:mouse/Duox1/Duox1-uniprot.txt SUBCELLULAR LOCATION: Apical cell membrane {ECO:0000250|UniProtKB:Q9NRD9}; Multi-pass membrane protein {ECO:0000269|PubMed:32929281}. |
| GO:0016174 NAD(P)H oxidase H2O2-forming activity | IBA GO_REF:0000033 | ACCEPT | Summary: Core catalytic activity of mouse DUOX1, transferring electrons from cytosolic NADPH via FAD and two transmembrane hemes to extracellular O2 to form H2O2. Reason: Core molecular function. Placed at the DUOX-specific PAINT node PTN000944147 and directly supported by biochemical reconstitution and cryo-EM structures of the mouse DUOX1-DUOXA1 complex (PMID:32929281). Supporting Evidence: PMID:32929281 One possible electron transfer pathway was identified as follows: NADPH β FAD β HEME #2 β Phe1097 β HEME #1. Accordingly, mutations of Phe1097 reduced H2O2 production (Extended Data Fig. 4f). file:mouse/Duox1/Duox1-uniprot.txt Reaction=NADPH + O2 + H(+) = H2O2 + NADP(+); |
| GO:0016174 NAD(P)H oxidase H2O2-forming activity | IEA GO_REF:0000003 | ACCEPT | Summary: Core catalytic activity of mouse DUOX1, transferring electrons from cytosolic NADPH via FAD and two transmembrane hemes to extracellular O2 to form H2O2. Reason: Core molecular function, consistent with the IBA, ISO, and ISS rows. Supporting Evidence: PMID:32929281 One possible electron transfer pathway was identified as follows: NADPH β FAD β HEME #2 β Phe1097 β HEME #1. Accordingly, mutations of Phe1097 reduced H2O2 production (Extended Data Fig. 4f). file:mouse/Duox1/Duox1-uniprot.txt Reaction=NADPH + O2 + H(+) = H2O2 + NADP(+); |
| GO:0016174 NAD(P)H oxidase H2O2-forming activity | ISO GO_REF:0000119 | ACCEPT | Summary: Core catalytic activity of mouse DUOX1, transferring electrons from cytosolic NADPH via FAD and two transmembrane hemes to extracellular O2 to form H2O2. Reason: Core molecular function, consistent with the IBA, IEA, and ISS rows. Supporting Evidence: PMID:32929281 One possible electron transfer pathway was identified as follows: NADPH β FAD β HEME #2 β Phe1097 β HEME #1. Accordingly, mutations of Phe1097 reduced H2O2 production (Extended Data Fig. 4f). file:mouse/Duox1/Duox1-uniprot.txt Reaction=NADPH + O2 + H(+) = H2O2 + NADP(+); |
| GO:0016174 NAD(P)H oxidase H2O2-forming activity | ISS GO_REF:0000024 | ACCEPT | Summary: Core catalytic activity of mouse DUOX1, transferring electrons from cytosolic NADPH via FAD and two transmembrane hemes to extracellular O2 to form H2O2. Reason: Core molecular function, consistent with the IBA, IEA, and ISO rows. Supporting Evidence: PMID:32929281 One possible electron transfer pathway was identified as follows: NADPH β FAD β HEME #2 β Phe1097 β HEME #1. Accordingly, mutations of Phe1097 reduced H2O2 production (Extended Data Fig. 4f). file:mouse/Duox1/Duox1-uniprot.txt Reaction=NADPH + O2 + H(+) = H2O2 + NADP(+); |
| GO:0016175 superoxide-generating NAD(P)H oxidase activity | IBA GO_REF:0000033 | MODIFY | Summary: Mature mouse DUOX1-DUOXA1 complexes generate hydrogen peroxide rather than superoxide; superoxide release is characteristic of the NOX branch seeding the deep ancestral node PTN000239643. Reason: Lateral correction matching human DUOX1. PAINT placed GO:0016175 at the deep NOX/DUOX ancestor PTN000239643 (seeded by NOX1, CYBB/NOX2, NOX3, NOX4, NOX5, and Dictyostelium NoxA/NoxB) and placed the H2O2-forming activity GO:0016174 at the DUOX-specific node PTN000944147. Mature mouse DUOX1-DUOXA1 produces H2O2 (PMID:32929281). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000239643 Β· deep NOX/DUOX ancestral node carrying the superoxide-generating IBD SUPPORTS SOURCE BUT NOT TARGET Seeded by NOX-branch oxidases (CYBB/NOX2, NOX1, NOX3, NOX4, NOX5); mature DUOX-DUOXA complexes in the descendant DUOX clade release H2O2 rather than superoxide. PANTHER:PTN000944147 Β· DUOX-specific node carrying the H2O2-forming IBD SUPPORTS TRANSFER Carries GO:0016174 (NAD(P)H oxidase H2O2-forming activity) for the DUOX clade including mouse Duox1. UniProtKB:P04839 Β· CYBB/NOX2 (human) SUPPORTS SOURCE BUT NOT TARGET Canonical superoxide-generating phagocyte NADPH oxidase; valid for the NOX branch but not for mature DUOX1-DUOXA1. Proposed replacements: NAD(P)H oxidase H2O2-forming activity Supporting Evidence: PMID:32929281 One possible electron transfer pathway was identified as follows: NADPH β FAD β HEME #2 β Phe1097 β HEME #1. Accordingly, mutations of Phe1097 reduced H2O2 production (Extended Data Fig. 4f). file:mouse/Duox1/Duox1-uniprot.txt Generates hydrogen peroxide (H2O2) which is required for the activity of thyroid peroxidase/TPO and lactoperoxidase/LPO (By similarity). |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: In polarized epithelial cells (airway epithelium and thyrocytes), DUOX1 localizes to the apical plasma membrane to release H2O2 into the lumen. Reason: Core subcellular location in polarized epithelia, where mouse Duox1 supplies H2O2 into the airway lumen for antiviral and antibacterial defense (PMID:34168077). Supporting Evidence: file:mouse/Duox1/Duox1-uniprot.txt SUBCELLULAR LOCATION: Apical cell membrane {ECO:0000250|UniProtKB:Q9NRD9}; Multi-pass membrane protein {ECO:0000269|PubMed:32929281}. Note=Localizes to the apical membrane of epithelial cells. |
| GO:0016324 apical plasma membrane | ISO GO_REF:0000119 | ACCEPT | Summary: In polarized epithelial cells, DUOX1 localizes to the apical plasma membrane to release H2O2 into the lumen. Reason: Core subcellular location in polarized epithelia, consistent with the IEA and ISS rows. Supporting Evidence: file:mouse/Duox1/Duox1-uniprot.txt SUBCELLULAR LOCATION: Apical cell membrane {ECO:0000250|UniProtKB:Q9NRD9}; Multi-pass membrane protein {ECO:0000269|PubMed:32929281}. Note=Localizes to the apical membrane of epithelial cells. |
| GO:0016324 apical plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: In polarized epithelial cells, DUOX1 localizes to the apical plasma membrane to release H2O2 into the lumen. Reason: Core subcellular location in polarized epithelia, consistent with the IEA and ISO rows. Supporting Evidence: file:mouse/Duox1/Duox1-uniprot.txt SUBCELLULAR LOCATION: Apical cell membrane {ECO:0000250|UniProtKB:Q9NRD9}; Multi-pass membrane protein {ECO:0000269|PubMed:32929281}. Note=Localizes to the apical membrane of epithelial cells. |
| GO:0016491 oxidoreductase activity | IEA GO_REF:0000002 | MODIFY | Summary: True but overly general InterPro2GO mapping; refined to the specific catalytic activity NAD(P)H oxidase H2O2-forming activity. Reason: Mouse Duox1 already carries the specific descendant term GO:0016174 (NAD(P)H oxidase H2O2-forming activity). Proposed replacements: NAD(P)H oxidase H2O2-forming activity Supporting Evidence: PMID:32929281 One possible electron transfer pathway was identified as follows: NADPH β FAD β HEME #2 β Phe1097 β HEME #1. Accordingly, mutations of Phe1097 reduced H2O2 production (Extended Data Fig. 4f). |
| GO:0019221 cytokine-mediated signaling pathway | IEA GO_REF:0000107 | MODIFY | Summary: Ortholog projection of a human annotation based on Th2 cytokine (IL-4/IL-13) transcriptional induction of DUOX1; DUOX1 responds to cytokines and promotes airway cytokine expression during viral challenge rather than transducing a cytokine receptor signaling pathway. Reason: Matches the human DUOX1 review. The underlying human IDA (PMID:16111680) assayed transcriptional upregulation of Duox1 by IL-4 and IL-13, which represents cellular response to cytokine stimulus (GO:0071345) rather than execution of a cytokine-mediated signaling pathway. Proposed replacements: cellular response to cytokine stimulus Supporting Evidence: PMID:34168077 Duox1 increases the airway levels of several cytokines (IL-1Ξ², IL-2, CCL1, CCL3, CCL11, CCL19, CCL20, CCL27, CXCL5, and CXCL11), contributes to innate immune cell recruitment, and affects epithelial apoptosis in the airways. |
| GO:0019221 cytokine-mediated signaling pathway | ISO GO_REF:0000119 | MODIFY | Summary: Ortholog projection of a human annotation based on Th2 cytokine (IL-4/IL-13) transcriptional induction of DUOX1; modified to cellular response to cytokine stimulus. Reason: Matches the human DUOX1 review and the IEA row above. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q9NRD9 Β· human DUOX1 SOURCE BAD The human source annotation (PMID:16111680) shows transcriptional induction of DUOX1 by IL-4/IL-13 (cellular response to cytokine stimulus, GO:0071345) rather than execution of a cytokine-mediated signaling pathway. Proposed replacements: cellular response to cytokine stimulus Supporting Evidence: PMID:34168077 Duox1 increases the airway levels of several cytokines (IL-1Ξ², IL-2, CCL1, CCL3, CCL11, CCL19, CCL20, CCL27, CXCL5, and CXCL11), contributes to innate immune cell recruitment, and affects epithelial apoptosis in the airways. |
| GO:0020037 heme binding | IDA PMID:32929281 Structures of mouse DUOX1-DUOXA1 provide mechanistic insight... | ACCEPT | Summary: Mouse DUOX1 binds two b-type heme groups orthogonally within transmembrane helices S2-S5 (coordinated by His1144/His1238 and His1130/His1225) that relay electrons across the membrane. Reason: Core cofactor binding directly resolved in the cryo-EM structures of the mouse DUOX1-DUOXA1 complex (PMID:32929281). Note that the two hemes are located in the transmembrane NOX core, whereas the N-terminal PHD binds no heme. Supporting Evidence: PMID:32929281 Two heme groups were observed in the TMD of DUOX1 (Fig. 3a). They are positioned almost orthogonally to the lipid bilayer and sandwiched within four continuous transmembrane helices S2βS5. PMID:32929281 The heme group on the extracellular side (HEME #1) is coordinated between His1144 of S3 and His1238 of S5, whereas the other one on the cytoplasmic side (HEME #2) is sandwiched between His1130 of S3 and His1225 of S5 (Fig. 3b). |
| GO:0020037 heme binding | IEA GO_REF:0000120 | ACCEPT | Summary: Mouse DUOX1 binds two b-type heme groups orthogonally within transmembrane helices S2-S5 that relay electrons across the membrane. Reason: Core cofactor binding, consistent with the IDA row from PMID:32929281 (note that the InterPro:IPR010255 peroxidase signature listed among supporting entities is a false trigger for the heme-less PHD, but heme binding is true of the protein via its transmembrane ferric-reductase domain). Supporting Evidence: PMID:32929281 Two heme groups were observed in the TMD of DUOX1 (Fig. 3a). They are positioned almost orthogonally to the lipid bilayer and sandwiched within four continuous transmembrane helices S2βS5. |
| GO:0020037 heme binding | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse DUOX1 binds two b-type heme groups orthogonally within transmembrane helices S2-S5 that relay electrons across the membrane. Reason: Core cofactor binding, consistent with the IDA row from PMID:32929281. Supporting Evidence: PMID:32929281 Two heme groups were observed in the TMD of DUOX1 (Fig. 3a). They are positioned almost orthogonally to the lipid bilayer and sandwiched within four continuous transmembrane helices S2βS5. |
| GO:0031252 cell leading edge | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: During epithelial wound repair and cell migration, DUOX1 is recruited to the leading edge of migrating cells. Reason: Matches the human DUOX1 review. Recruitment to the cell leading edge during wound repair is a stimulus-specific relocalization secondary to its primary apical plasma membrane location in polarized epithelia. Supporting Evidence: PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0031252 cell leading edge | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: During epithelial wound repair and cell migration, DUOX1 is recruited to the leading edge of migrating cells. Reason: Stimulus-specific relocalization during epithelial migration, consistent with the IEA row. Supporting Evidence: PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:0032757 positive regulation of interleukin-8 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog projection from human DUOX1, where H2O2 generated by DUOX1 promotes downstream epithelial chemokine (CXCL8/IL-8 in human; functional CXC chemokine homologs such as CXCL5/CXCL11 in mouse) production. Reason: Matches the human DUOX1 review. Downstream redox-signaling consequence of DUOX1-derived H2O2 in airway epithelium (and in mice, Duox1 similarly promotes CXCL5/CXCL11 and inflammatory cytokine production in the airways, PMID:34168077). Supporting Evidence: PMID:34168077 Duox1 increases the airway levels of several cytokines (IL-1Ξ², IL-2, CCL1, CCL3, CCL11, CCL19, CCL20, CCL27, CXCL5, and CXCL11), contributes to innate immune cell recruitment, and affects epithelial apoptosis in the airways. |
| GO:0032757 positive regulation of interleukin-8 production | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Ortholog projection from human DUOX1, where DUOX1-derived H2O2 promotes downstream epithelial chemokine production. Reason: Downstream redox-signaling consequence of DUOX1-derived H2O2, consistent with the IEA and ISS rows. Supporting Evidence: PMID:34168077 Duox1 increases the airway levels of several cytokines (IL-1Ξ², IL-2, CCL1, CCL3, CCL11, CCL19, CCL20, CCL27, CXCL5, and CXCL11), contributes to innate immune cell recruitment, and affects epithelial apoptosis in the airways. |
| GO:0032757 positive regulation of interleukin-8 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity projection from human DUOX1, where DUOX1-derived H2O2 promotes downstream epithelial chemokine production. Reason: Downstream redox-signaling consequence of DUOX1-derived H2O2, consistent with the IEA and ISO rows. Supporting Evidence: PMID:34168077 Duox1 increases the airway levels of several cytokines (IL-1Ξ², IL-2, CCL1, CCL3, CCL11, CCL19, CCL20, CCL27, CXCL5, and CXCL11), contributes to innate immune cell recruitment, and affects epithelial apoptosis in the airways. |
| GO:0042335 cuticle development | IEA GO_REF:0000107 | REMOVE | Summary: Taxonomically invalid propagation of nematode-specific cuticle cross-linking (C. elegans BLI-3) via human DUOX1 to mouse Duox1. Reason: Mammals do not possess an extracellular collagenous cuticle. As documented in the human DUOX1 review, human DUOX1 was annotated to GO:0042335 from a C. elegans bli-3 RNAi loss-of-function phenotype in PMID:11514595 (Edens et al., 2001), and Ensembl Compara (GO_REF:0000107) and MGI ISO (GO_REF:0000119) propagated that erroneous annotation onto mouse Duox1. Furthermore, the cryo-EM structure of mouse DUOX1 (PMID:32929281) proves its PHD lacks heme and cannot catalyze the peroxidase reaction required for cuticle dityrosine cross-linking. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: UniProtKB:Q9NRD9 Β· human DUOX1 SOURCE BAD Human DUOX1 carries GO:0042335 only from a C. elegans bli-3 RNAi loss-of-function study (PMID:11514595, Edens et al., 2001); neither humans nor mice have a nematode cuticle, and mammalian DUOX1 lacks heme in its PHD. Supporting Evidence: PMID:32929281 Though the PHD of DUOX1 has an overall architecture of peroxidase with an RMSD of 1.3 Γ
when superimposed with the bovine lactoperoxidase (LPO, PDB 5B72) (Extended Data Fig. 2a)21, the facts that no heme density is observed in the cryo-EM map and histidines needed for heme coordination are missing in the putative binding pocket strongly suggest that the PHD domain of DUOX1 lacks heme-dependent peroxidase activity. |
| GO:0042335 cuticle development | ISO GO_REF:0000119 | REMOVE | Summary: Taxonomically invalid MGI orthology transfer of nematode-specific cuticle development from human DUOX1 to mouse Duox1. Reason: Same failure mode as the GO_REF:0000107 IEA row: mammals lack a collagenous cuticle, and the source annotation on human DUOX1 is itself an artifact of C. elegans bli-3 cross-annotation. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: UniProtKB:Q9NRD9 Β· human DUOX1 SOURCE BAD Human DUOX1 does not perform cuticle development; transferring this annotation to mouse Duox1 via ISO propagates an upstream curation error across mammals. Supporting Evidence: PMID:32929281 Though the PHD of DUOX1 has an overall architecture of peroxidase with an RMSD of 1.3 Γ
when superimposed with the bovine lactoperoxidase (LPO, PDB 5B72) (Extended Data Fig. 2a)21, the facts that no heme density is observed in the cryo-EM map and histidines needed for heme coordination are missing in the putative binding pocket strongly suggest that the PHD domain of DUOX1 lacks heme-dependent peroxidase activity. |
| GO:0042554 superoxide anion generation | IBA GO_REF:0000033 | MODIFY | Summary: Deep PANTHER family IBA (`PTN000239643`) asserting superoxide anion generation; mature mouse DUOX1-DUOXA1 complexes dismutate superoxide internally and release H2O2 as their physiological product. Reason: Matches the human DUOX1 review. Mature DUOX1-DUOXA1 complexes synthesize and release hydrogen peroxide (GO:0050665, which mouse Duox1 already carries by IDA from PMID:32929281) rather than free superoxide. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000239643 Β· deep NOX/DUOX ancestral node carrying the superoxide-generating IBD SUPPORTS SOURCE BUT NOT TARGET Placed at the deep NOX/DUOX root based on superoxide-producing NOX enzymes (CYBB/NOX2, NOX1, NOX3, NOX5), whereas the DUOX clade evolved obligate heterodimerization with DUOXA to release H2O2 directly. UniProtKB:P04839 Β· CYBB/NOX2 (human) SUPPORTS SOURCE BUT NOT TARGET Generates extracellular superoxide in phagocytes; does not reflect the H2O2-forming activity of the DUOX1-DUOXA1 complex. Proposed replacements: hydrogen peroxide biosynthetic process Supporting Evidence: PMID:32929281 One possible electron transfer pathway was identified as follows: NADPH β FAD β HEME #2 β Phe1097 β HEME #1. Accordingly, mutations of Phe1097 reduced H2O2 production (Extended Data Fig. 4f). |
| GO:0043020 NADPH oxidase complex | IBA GO_REF:0000033 | ACCEPT | Summary: Mouse DUOX1 is the catalytic subunit of the DUOX1-DUOXA1 NADPH oxidase complex (assembled as a 1:1 heterodimer or 2:2 dimer-of-heterodimers). Reason: Core complex membership directly resolved in the cryo-EM structures of the mouse DUOX1-DUOXA1 complex (PMID:32929281). Note that mouse Duox1 (MGI:MGI:2139422) appears in its own IBA WITH/FROM list because its experimental IPI annotation from PMID:32929281 is one of the PAINT seeds. Supporting Evidence: PMID:32929281 Here I report cryo-EM structures of mouse DUOX1βDUOXA1 complexes in NADPH-free, NADPH-bound and dimer-of-dimer states, providing structural mechanisms underlying DUOX1βDUOXA1 activation and regulation and molecular insights into ROS production. |
| GO:0043020 NADPH oxidase complex | IEA GO_REF:0000107 | ACCEPT | Summary: Mouse DUOX1 is the catalytic subunit of the DUOX1-DUOXA1 NADPH oxidase complex. Reason: Core complex membership, consistent with the IPI row from PMID:32929281. Supporting Evidence: PMID:32929281 Here I report cryo-EM structures of mouse DUOX1βDUOXA1 complexes in NADPH-free, NADPH-bound and dimer-of-dimer states, providing structural mechanisms underlying DUOX1βDUOXA1 activation and regulation and molecular insights into ROS production. |
| GO:0043020 NADPH oxidase complex | IPI PMID:32929281 Structures of mouse DUOX1-DUOXA1 provide mechanistic insight... | ACCEPT | Summary: Cryo-EM structures of the mouse DUOX1-DUOXA1 complex establish that DUOX1 and DUOXA1 form a stable NADPH oxidase complex in both 1:1 heterodimer and 2:2 dimer-of-heterodimer configurations. Reason: Direct structural evidence (3.2-3.3 A cryo-EM) of the mouse DUOX1-DUOXA1 NADPH oxidase complex (PMID:32929281). Supporting Evidence: PMID:32929281 Here I report cryo-EM structures of mouse DUOX1βDUOXA1 complexes in NADPH-free, NADPH-bound and dimer-of-dimer states, providing structural mechanisms underlying DUOX1βDUOXA1 activation and regulation and molecular insights into ROS production. |
| GO:0043020 NADPH oxidase complex | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse DUOX1 is the catalytic subunit of the DUOX1-DUOXA1 NADPH oxidase complex. Reason: Core complex membership, consistent with the IPI row from PMID:32929281. Supporting Evidence: PMID:32929281 Here I report cryo-EM structures of mouse DUOX1βDUOXA1 complexes in NADPH-free, NADPH-bound and dimer-of-dimer states, providing structural mechanisms underlying DUOX1βDUOXA1 activation and regulation and molecular insights into ROS production. |
| GO:0046982 protein heterodimerization activity | IPI PMID:32929281 Structures of mouse DUOX1-DUOXA1 provide mechanistic insight... | ACCEPT | Summary: Mouse DUOX1 directly heterodimerizes with its maturation factor DUOXA1 (UniProtKB:Q8VE49) via extensive extracellular and transmembrane interfaces required for ER exit and H2O2 production. Reason: Directly demonstrated by 3.2 A cryo-EM structure and interface mutagenesis of the mouse DUOX1-DUOXA1 heterodimer (PMID:32929281). Supporting Evidence: PMID:32929281 DUOX1 and DUOXA1 interact via three interfaces (Fig. 2). Interface #1, involving PHD of DUOX1 and the extracellular domain of DUOXA1, buries a surface area of ~987 Γ
2. |
| GO:0050665 hydrogen peroxide biosynthetic process | IDA PMID:32929281 Structures of mouse DUOX1-DUOXA1 provide mechanistic insight... | ACCEPT | Summary: Co-expression of mouse DUOX1 with DUOXA1 directly synthesizes extracellular hydrogen peroxide via transmembrane electron transfer from NADPH through FAD and two hemes. Reason: Core biological process of DUOX1 directly assayed and structurally characterized in PMID:32929281. Supporting Evidence: PMID:32929281 One possible electron transfer pathway was identified as follows: NADPH β FAD β HEME #2 β Phe1097 β HEME #1. Accordingly, mutations of Phe1097 reduced H2O2 production (Extended Data Fig. 4f). |
| GO:0050665 hydrogen peroxide biosynthetic process | IEA GO_REF:0000107 | ACCEPT | Summary: Mouse DUOX1 synthesizes extracellular hydrogen peroxide in complex with DUOXA1. Reason: Core biological process, consistent with the IDA row from PMID:32929281. Supporting Evidence: PMID:32929281 One possible electron transfer pathway was identified as follows: NADPH β FAD β HEME #2 β Phe1097 β HEME #1. Accordingly, mutations of Phe1097 reduced H2O2 production (Extended Data Fig. 4f). |
| GO:0050665 hydrogen peroxide biosynthetic process | ISO GO_REF:0000096 | ACCEPT | Summary: Mouse DUOX1 synthesizes extracellular hydrogen peroxide in complex with DUOXA1. Reason: Core biological process, consistent with the IDA row from PMID:32929281. Supporting Evidence: PMID:32929281 One possible electron transfer pathway was identified as follows: NADPH β FAD β HEME #2 β Phe1097 β HEME #1. Accordingly, mutations of Phe1097 reduced H2O2 production (Extended Data Fig. 4f). |
| GO:0050665 hydrogen peroxide biosynthetic process | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse DUOX1 synthesizes extracellular hydrogen peroxide in complex with DUOXA1. Reason: Core biological process, consistent with the IDA row from PMID:32929281. Supporting Evidence: PMID:32929281 One possible electron transfer pathway was identified as follows: NADPH β FAD β HEME #2 β Phe1097 β HEME #1. Accordingly, mutations of Phe1097 reduced H2O2 production (Extended Data Fig. 4f). |
| GO:0051591 response to cAMP | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ortholog projection from human DUOX1, which is induced at the protein level by the adenylyl cyclase activator forskolin. Reason: Matches the human DUOX1 review. Curated CC:INDUCTION on human DUOX1 (Q9NRD9) documents protein-level induction by forskolin (cAMP/PKA pathway), although human DUOX1/DUOX2 promoter studies show that basal promoter transcription itself is not positively controlled by cAMP in human thyrocytes (PMID:15062544). Retained as non-core upstream regulatory responsiveness rather than the primary enzymatic process executed by DUOX1. 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 | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Ortholog projection from human DUOX1, which is induced at the protein level by forskolin. Reason: Upstream regulatory responsiveness to cAMP/PKA signaling (with the human promoter caveat in PMID:15062544), consistent with the IEA row. 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:32929281 Structures of mouse DUOX1-DUOXA1 provide mechanistic insight... | ACCEPT | Summary: The C-terminal cytoplasmic dehydrogenase domain of mouse DUOX1 binds the electron donor NADPH, directly visualized by cryo-EM at 3.2-3.3 A resolution. Reason: Core substrate/cofactor binding directly resolved in the cryo-EM structures of the mouse DUOX1-DUOXA1 complex (PMID:32929281). Supporting Evidence: PMID:32929281 The map shows a potential density corresponding to an NADPH molecule in the NBD (Fig. 4a and Extended Data Fig. 4a). This extra density permits modeling of the βphosphor-ADP-riboseβ part of NADPH, while there is little density for the nicotinamide group (Fig. 4a and Extended Data Fig. 4b,c). |
| GO:0070402 NADPH binding | IEA GO_REF:0000107 | ACCEPT | Summary: Mouse DUOX1 binds NADPH in its C-terminal dehydrogenase domain. Reason: Core substrate/cofactor binding, consistent with the IDA row from PMID:32929281. Supporting Evidence: PMID:32929281 The map shows a potential density corresponding to an NADPH molecule in the NBD (Fig. 4a and Extended Data Fig. 4a). This extra density permits modeling of the βphosphor-ADP-riboseβ part of NADPH, while there is little density for the nicotinamide group (Fig. 4a and Extended Data Fig. 4b,c). |
| GO:0070402 NADPH binding | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse DUOX1 binds NADPH in its C-terminal dehydrogenase domain. Reason: Core substrate/cofactor binding, consistent with the IDA row from PMID:32929281. Supporting Evidence: PMID:32929281 The map shows a potential density corresponding to an NADPH molecule in the NBD (Fig. 4a and Extended Data Fig. 4a). This extra density permits modeling of the βphosphor-ADP-riboseβ part of NADPH, while there is little density for the nicotinamide group (Fig. 4a and Extended Data Fig. 4b,c). |
| GO:0071949 FAD binding | IDA PMID:32929281 Structures of mouse DUOX1-DUOXA1 provide mechanistic insight... | ACCEPT | Summary: Mouse DUOX1 binds the flavin cofactor FAD in the cleft between the FBD and NBD of its C-terminal dehydrogenase domain, directly visualized by cryo-EM. Reason: Core cofactor binding directly resolved in the cryo-EM structures of the mouse DUOX1-DUOXA1 complex (PMID:32929281). Supporting Evidence: PMID:32929281 Cryo-EM density consistent with a FAD molecule was identified in a positively charged pocket at the interface between transmembrane and cytoplasmic domains (Fig. 3c,d and Extended Data Fig. 3c). On the cytoplasmic side, the FAD-binding site is mainly formed by residues from the FBD (Fig. 3d). |
| GO:0071949 FAD binding | IEA GO_REF:0000107 | ACCEPT | Summary: Mouse DUOX1 binds the flavin cofactor FAD in its C-terminal dehydrogenase domain. Reason: Core cofactor binding, consistent with the IDA row from PMID:32929281. Supporting Evidence: PMID:32929281 Cryo-EM density consistent with a FAD molecule was identified in a positively charged pocket at the interface between transmembrane and cytoplasmic domains (Fig. 3c,d and Extended Data Fig. 3c). On the cytoplasmic side, the FAD-binding site is mainly formed by residues from the FBD (Fig. 3d). |
| GO:0071949 FAD binding | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse DUOX1 binds the flavin cofactor FAD in its C-terminal dehydrogenase domain. Reason: Core cofactor binding, consistent with the IDA row from PMID:32929281. Supporting Evidence: PMID:32929281 Cryo-EM density consistent with a FAD molecule was identified in a positively charged pocket at the interface between transmembrane and cytoplasmic domains (Fig. 3c,d and Extended Data Fig. 3c). On the cytoplasmic side, the FAD-binding site is mainly formed by residues from the FBD (Fig. 3d). |
| GO:0072593 reactive oxygen species metabolic process | IEA GO_REF:0000117 | MODIFY | Summary: True but overly general ARBA rule annotation; refined to the specific descendant process hydrogen peroxide biosynthetic process. Reason: Mouse Duox1 already carries the specific descendant term GO:0050665 (hydrogen peroxide biosynthetic process) via direct experimental evidence (PMID:32929281). Proposed replacements: hydrogen peroxide biosynthetic process Supporting Evidence: PMID:32929281 One possible electron transfer pathway was identified as follows: NADPH β FAD β HEME #2 β Phe1097 β HEME #1. Accordingly, mutations of Phe1097 reduced H2O2 production (Extended Data Fig. 4f). |
| GO:0072593 reactive oxygen species metabolic process | IGI PMID:20233719 Mammalian numb-interacting protein 1/dual oxidase maturation... | MODIFY | Summary: Mouse neural stem cell differentiation study showing Nip1/Duoxa1 directs Duox1-mediated ROS/H2O2 production; the generic ROS metabolic process term is refined to hydrogen peroxide biosynthetic process. Reason: Kennedy et al. (PMID:20233719) demonstrated that Nip1 (Duoxa1, MGI:2384861) interacts with Duox1 to drive Duox1-mediated ROS/H2O2 production in neural stem cells. GO:0072593 is overly broad given that mouse Duox1 directly catalyzes hydrogen peroxide biosynthesis (GO:0050665), and replacement with GO:0050665 should also refine the qualifier from acts_upstream_of_or_within to involved_in. Proposed replacements: hydrogen peroxide biosynthetic process Supporting Evidence: PMID:20233719 The highest expression of Nip1 was observed in undifferentiated neuronal stem cells and was associated with Duox1-mediated reactive oxygen species ROS production. |
| GO:0090303 positive regulation of wound healing | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: DUOX1-generated H2O2 promotes epithelial cell migration and wound repair in response to extracellular ATP and Ca2+ signaling. Reason: Matches the human DUOX1 review. Downstream physiological effect of DUOX1-derived H2O2 signaling in damaged epithelia. 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 | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: DUOX1-generated H2O2 promotes epithelial cell migration and wound repair. Reason: Downstream physiological effect of DUOX1-derived H2O2 signaling in damaged epithelia, consistent with the IEA row. 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-generated H2O2 in the airway lumen supports the mucosal antiviral innate immune response against influenza A virus, reducing morbidity, mortality, and viral load in mice. Reason: Well-supported physiological role in mouse respiratory epithelium (PMID:34168077), kept as non-core relative to the primary enzymatic process of hydrogen peroxide biosynthesis (GO:0050665), consistent with the human DUOX1 review. Supporting Evidence: PMID:34168077 Here, we show that Duox1 promotes antiviral innate immunity in vivo. Upon influenza airway challenge, Duox1-/- mice have enhanced mortality, morbidity, and impaired lung viral clearance. |
| GO:0140374 antiviral innate immune response | IMP PMID:34168077 Dual oxidase 1 promotes antiviral innate immunity. | KEEP AS NON CORE | Summary: Duox1-deficient mice exhibit significantly increased morbidity, mortality, and lung viral loads upon intranasal challenge with H1N1 influenza A virus, demonstrating a protective role in airway antiviral innate immunity. Reason: Direct in vivo mouse knockout phenotype (PMID:34168077); kept as non-core downstream physiological role of Duox1-derived H2O2 in the airway lumen, matching the human DUOX1 review. Supporting Evidence: PMID:34168077 Here, we show that Duox1 promotes antiviral innate immunity in vivo. Upon influenza airway challenge, Duox1-/- mice have enhanced mortality, morbidity, and impaired lung viral clearance. |
| GO:0140374 antiviral innate immune response | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: DUOX1-generated H2O2 in the airway lumen supports the mucosal antiviral innate immune response. Reason: Downstream physiological role in airway innate immunity, consistent with the IMP row from PMID:34168077. Supporting Evidence: PMID:34168077 Here, we show that Duox1 promotes antiviral innate immunity in vivo. Upon influenza airway challenge, Duox1-/- mice have enhanced mortality, morbidity, and impaired lung viral clearance. |
| GO:1900426 positive regulation of defense response to bacterium | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: DUOX1-generated H2O2 fuels the airway lactoperoxidase (LPO) antimicrobial system to generate microbicidal hypothiocyanite (OSCN-) against mucosal bacteria. Reason: Matches the human DUOX1 review. Downstream mucosal antibacterial defense consequence of luminal H2O2 generation by DUOX1. Supporting Evidence: PMID:34168077 While a line of prior in vitro observations suggested that DUOX1 works in partnership with an airway peroxidase, lactoperoxidase (LPO), to produce antimicrobial hypothiocyanite (OSCN-) in the airways, the in vivo role of DUOX1 in mammalian organisms has remained unproven to date. |
| GO:1900426 positive regulation of defense response to bacterium | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: DUOX1-generated H2O2 fuels the airway lactoperoxidase antimicrobial system in defense against bacteria. Reason: Downstream mucosal antibacterial defense consequence of luminal H2O2 generation, consistent with the IEA and ISS rows. Supporting Evidence: PMID:34168077 While a line of prior in vitro observations suggested that DUOX1 works in partnership with an airway peroxidase, lactoperoxidase (LPO), to produce antimicrobial hypothiocyanite (OSCN-) in the airways, the in vivo role of DUOX1 in mammalian organisms has remained unproven to date. |
| GO:1900426 positive regulation of defense response to bacterium | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: DUOX1-generated H2O2 fuels the airway lactoperoxidase antimicrobial system in defense against bacteria. Reason: Downstream mucosal antibacterial defense consequence of luminal H2O2 generation, consistent with the IEA and ISO rows. Supporting Evidence: PMID:34168077 While a line of prior in vitro observations suggested that DUOX1 works in partnership with an airway peroxidase, lactoperoxidase (LPO), to produce antimicrobial hypothiocyanite (OSCN-) in the airways, the in vivo role of DUOX1 in mammalian organisms has remained unproven to date. |
| GO:2000147 positive regulation of cell motility | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: DUOX1-derived H2O2 promotes epithelial cell migration during wound repair. Reason: Matches the human DUOX1 review. Downstream cellular consequence of DUOX1-derived H2O2 signaling in migrating epithelial cells. Supporting Evidence: PMID:19339556 Functional Duox1 and Duox2 localize to the leading edge of migrating cells, augmenting motility and wound healing. |
| GO:2000147 positive regulation of cell motility | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: DUOX1-derived H2O2 promotes epithelial cell migration during wound repair. Reason: Downstream cellular consequence of DUOX1-derived H2O2 signaling in migrating epithelial cells, consistent with the IEA row. 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: While DUOX2 is the primary H2O2 generator for thyroid hormone biosynthesis, DUOX1 is co-expressed in thyrocytes and provides auxiliary H2O2 without causing overt hypothyroidism when deleted alone in mice. Reason: Secondary/auxiliary physiological role in the thyroid (where DUOX2 is dominant and Duox1-/- mice are euthyroid), consistent with the author statement in PMID:25761904. Supporting Evidence: PMID:25761904 As H2O2 generator, it plays a key role in both thyroid hormone biosynthesis and innate immunity. |
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Download this section (compressed HTML)Q: How does the interface between the DUOX1 extracellular loops, the N-terminal PHD, and the extracellular region of DUOXA1 retain superoxide for rapid intramolecular dismutation to H2O2?
Suggested experts: Jiaxuan Wu, Lei Chen, Miklos Geiszt
Q: Does the transition between the inactive 2:2 dimer-of-heterodimers and the active 1:1 DUOX1-DUOXA1 heterodimer occur dynamically upon Ca2+ and PKA activation in native mouse airway epithelial cells?
Suggested experts: Jiaxuan Wu, Lei Chen, Balazs Rada
Experiment: Determine high-resolution cryo-EM structures of the mouse DUOX1-DUOXA1 heterodimer in the presence of saturating Ca2+ and PKA phosphorylation (or phosphomimetic mutations) to visualize the Ca2+-bound EF-hand domain and the active-state docking of the dehydrogenase domain against the transmembrane heme core.
Hypothesis: Ca2+ binding to the EF1 and EF2 motifs orders the mobile intracellular loop and stabilizes the productive electron-transfer distance between the FAD isoalloxazine ring and HEME #2.
Type: Cryo-EM single-particle reconstruction of Ca2+-bound, phosphorylated mouse DUOX1-DUOXA1 in lipid nanodiscs.
Experiment: Single-molecule subunit-counting fluorescence microscopy of endogenously tagged Duox1-mNeonGreen and Duoxa1-HaloTag in polarized mouse tracheal epithelial cells before and after purinergic (ATP/ionomycin) stimulation.
Hypothesis: Agonist-evoked Ca2+ influx shifts the equilibrium at the apical plasma membrane between 2:2 dimers-of-heterodimers and active 1:1 heterodimers.
Type: Total internal reflection / apical sheet single-molecule photobleaching and FΓΆrster resonance energy transfer (smFRET) in primary mouse tracheal air-liquid interface cultures.
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