Affinage

CYBB

NADPH oxidase 2 · UniProt P04839

Length
570 aa
Mass
65.3 kDa
Annotated
2026-06-09
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CYBB (gp91phox/NOX2) encodes the catalytic, heme-binding transmembrane subunit of the phagocyte NADPH oxidase, the enzyme system that transfers electrons from cytoplasmic NADPH through FAD to molecular oxygen to generate superoxide (PMID:9653128, PMID:10627478). gp91phox is the sole heme-binding subunit of flavocytochrome b558, carrying two non-equivalent heme groups, and assembles as a 1:1 heterodimer with p22phox, with both subunits required for stable biosynthesis and functional oxidase reconstitution with neutrophil cytosol (PMID:9653128, PMID:8527449, PMID:8615831). Catalysis is governed by discrete residues in the FAD-binding domain that mediate hydride transfer from NADPH and by domains required for cytosolic subunit (p47phox/p67phox) translocation; missense mutations in these regions abolish electron transfer and underlie X-linked chronic granulomatous disease (X-CGD), which is corrected by restoring functional gp91phox expression (PMID:10627478, PMID:8781441, PMID:28153086). Enzyme assembly and output are tuned by post-translational control: PKC phosphorylates the cytosolic flavoprotein domain to enhance diaphorase activity and binding of Rac2, p67phox, and p47phox (PMID:19028840), a Rac-dependent redox feedforward loop drives the characteristic oxidative burst kinetics (PMID:34293347), p40phox stabilizes the resting state as a negative regulator (PMID:10672014), and ATM-dependent phosphorylation at Ser486 within the NOX2 insertion sequence down-regulates activity (PMID:28916473). CYBB transcription in myeloid cells is controlled by a lineage-restricted factor network — Ets factors PU.1 and Elf-1, IRF-1, ICSBP, STAT-1, YY1, and HoxA9 acting as activators, with CDP and HoxA10 as repressors — integrated through IFN-γ/JAK2 signaling and antagonized by the tyrosine phosphatases SHP1 and SHP2 (PMID:1885602, PMID:9593745, PMID:11781315, PMID:7713934, PMID:10233904, PMID:10514482, PMID:15681849, PMID:17138561, PMID:15496449). Beyond antimicrobial superoxide production, NOX2-derived ROS act as a signaling output across cell types: they promote endosomal TRAF6 recruitment to drive IL-1R/NF-κB signaling (PMID:16354686), mediate NMDA-receptor-dependent neuronal ROS via an nNOS/cGMP/PKG pathway (PMID:19244529), support LC3-associated phagocytosis and MHC-II antigen presentation in dendritic cells (PMID:37175412), drive macrophage macropinocytosis through PI3K/Akt and cofilin (PMID:27488058), and form a stable TRPC3-Nox2 complex in cardiomyocytes that mediates stress-induced atrophy (PMID:28768915, PMID:31278358).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1995 High

    Establishing the subunit architecture of cytochrome b558 was needed to define the core oxidase module; quantitative sequencing fixed the gp91phox:p22phox stoichiometry at 1:1.

    Evidence Affinity purification of native cytochrome b558 from neutrophil membranes with quantitative N-terminal sequencing

    PMID:8527449

    Open questions at the time
    • Does not localize the heme groups or define the electron transfer path
    • Stoichiometry in non-phagocytic cells not addressed
  2. 1998 High

    It was unclear which subunit carried the redox cofactors; expression of gp91phox alone reconstituted the full b558 heme spectrum, proving gp91phox is the sole heme-binding catalytic subunit while both subunits are needed for superoxide production.

    Evidence Heterologous COS7 expression with spectral/redox titration and cell-free superoxide assay

    PMID:9653128

    Open questions at the time
    • Atomic-resolution heme coordination not resolved
    • Mechanism of p22phox contribution to activity not defined
  3. 2000 High

    How specific residues control catalysis versus assembly was unknown; X-CGD missense mutations separated translocation-defective residues from a FAD-domain residue (Thr341) required for hydride transfer.

    Evidence Patient missense mutations analyzed by cell-free translocation and electron transfer assays in solubilized membranes

    PMID:10627478

    Open questions at the time
    • Full structural basis of electron flow not mapped
    • Does not address regulatory phosphorylation
  4. 2000 High

    The resting-state control of the assembled oxidase was unclear; p40phox was shown to act as a negative regulator that must dissociate from p67phox for activity.

    Evidence Cell-free reconstitution with purified components and recombinant p40phox in p67phox-deficient CGD model

    PMID:10672014

    Open questions at the time
    • In vivo dynamics of p40phox release not defined
    • Single-lab cell-free system
  5. 2008 High

    Post-translational activation of the catalytic subunit was poorly defined; PKC phosphorylation of the gp91phox cytosolic flavoprotein domain was shown to enhance diaphorase activity and cytosolic subunit binding.

    Evidence In vitro PKC phosphorylation of recombinant domain, 2D peptide mapping, binding and diaphorase assays with CGD controls

    PMID:19028840

    Open questions at the time
    • Exact phosphosites within the domain not enumerated here
    • Quantitative contribution to cellular burst not established
  6. 2017 High

    A mechanism limiting oxidase output was unknown; ATM-dependent Ser486 phosphorylation within the NOX2 insertion sequence was identified as a deactivating modification, and the NIS itself was shown essential for activity and subunit translocation.

    Evidence NIS chimera/deletion, MS phosphosite mapping, Ser486 point mutants, ATM inhibitor in PLB-985 cells

    PMID:28916473

    Open questions at the time
    • Physiological trigger linking ATM to NOX2 not fully defined
    • Structural role of NIS not resolved
  7. 2021 High

    The kinetics of the oxidative burst lacked a mechanistic explanation; a Rac-dependent redox feedforward loop was shown to account for ~98% of NOX2 activation.

    Evidence Mutagenesis of Rac redox-sensitive residues with kinetic O2- and cell-based ROS assays

    PMID:34293347

    Open questions at the time
    • In vivo relevance across cell types not established
    • Identity of the redox sensor on Rac not fully defined
  8. 2005 High

    How CYBB transcription is restricted to mature myeloid cells and induced by IFN-γ was being assembled; a network of activators (PU.1, Elf-1, IRF-1, ICSBP, STAT-1, YY1, HoxA9) and repressors (CDP, HoxA10) acting on the proximal promoter, modulated by JAK2, SHP1, and SHP2, was defined.

    Evidence EMSA, reporter assays, reconstitution with in vitro translated factors, phosphosite mutagenesis, and phosphatase/kinase manipulation across myeloid cell lines (consolidated 1991–2006)

    PMID:10233904 PMID:10514482 PMID:11483597 PMID:11781315 PMID:15496449 PMID:15681849 PMID:17138561 PMID:1885602 PMID:7713934 PMID:9593745

    Open questions at the time
    • Chromatin/epigenetic state of the locus not addressed in most studies
    • Relative in vivo contribution of each factor not weighted
  9. 2017 Medium

    Whether CYBB regulatory requirements extend beyond the promoter was unknown; gene-editing in X-CGD iPSCs showed that intron 1 sequences are necessary for endogenous CYBB expression and that exon repair restores ROS production.

    Evidence TALEN/Cas9 editing and minigene insertion in patient iPSCs with granulocyte differentiation and oxidative burst readouts

    PMID:28153086

    Open questions at the time
    • Specific intron 1 regulatory element not mapped
    • Single-lab gene-editing study
  10. 2009 High

    Whether NOX2 functions as a signaling source rather than only an antimicrobial enzyme was unresolved; endosomal NOX2-derived ROS were shown to drive TRAF6 recruitment for IL-1R/NF-κB activation, and a NOX2/TRX-1/NF-κB axis links NOX2 to inflammatory control.

    Evidence siRNA knockdowns, endosomal ROS measurement, co-IP of signaling complexes and TRX-1/p40phox, NF-κB readouts, CGD patient cells (consolidated)

    PMID:16354686 PMID:27698473

    Open questions at the time
    • Spatial source of ROS within endosomes not fully resolved
    • Generalizability across receptor systems untested
  11. 2009 High

    A neuronal NOX2 function was undefined; NMDA receptor activation was shown to generate postsynaptic ROS through a NOX2 oxidase acting downstream of nNOS/cGMP/PKG.

    Evidence In vivo NMDA application with ROS measurement in NOX2-KO mice, EM localization, neuronal culture pharmacology

    PMID:19244529

    Open questions at the time
    • Downstream neuronal targets of ROS not identified
    • Behavioral consequences not addressed
  12. 2020 High

    Roles for CYBB in adaptive immunity and tissue remodeling were emerging; conditional and global studies placed CYBB in LC3-associated phagocytosis/antigen presentation, macrophage macropinocytosis, osteoclast differentiation, and neutrophil-mediated muscle injury.

    Evidence Conditional cDC Cybb KO with EAE transfer, Nox2 KO/siRNA with PI3K/cofilin and NFATc1 readouts, gp91phox-null muscle injury models (consolidated)

    PMID:14555723 PMID:27488058 PMID:27897222 PMID:32401602

    Open questions at the time
    • Molecular ROS targets in each pathway only partially defined
    • Cell-type-specific regulation of NOX2 output not unified
  13. 2019 High

    Whether NOX2 acts through stable partner complexes in non-phagocytic tissues was unknown; a stable TRPC3-Nox2 complex was shown to mediate cardiomyocyte ROS overproduction and atrophy under doxorubicin and nutritional/ATP stress.

    Evidence Co-IP of TRPC3-Nox2, dominant-negative minipeptide, dual knockdown, ROS and atrophy assays, TRPC3-KO mice (consolidated)

    PMID:28768915 PMID:31278358

    Open questions at the time
    • Structural basis of TRPC3-Nox2 coupling not resolved
    • Whether cytosolic subunits participate in this complex not defined
  14. 2021 Medium

    Pathogenic roles for NOX2-derived ROS in cancer and metabolic disease were emerging; CYBB was linked to TAZ-driven oxidative DNA damage in NASH-HCC, a CYBB/Nrf2/SOD2 ferroptosis-resistance axis in glioblastoma, and a NOX2/FOXC1 self-renewal program in leukemic stem cells.

    Evidence In vivo shCybb silencing with DNA-repair rescue, CYBB-Nrf2 co-IP with ferroptosis assays, NOX2/FOXC1 epistasis in leukemia xenografts (consolidated)

    PMID:30943405 PMID:34902531 PMID:37175412

    Open questions at the time
    • Direct ROS targets driving each oncogenic phenotype not fully mapped
    • Single-lab studies for each context

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NOX2 output is spatially and contextually channeled — selecting between antimicrobial killing, discrete redox signaling, and pathological ROS — across phagocytic and non-phagocytic cells remains unresolved.
  • No unified model linking subcellular localization to functional output
  • Determinants of partner choice (e.g., TRPC3 vs cytosolic subunits) unknown
  • Atomic structure of the assembled active oxidase not described in this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 2 GO:0005768 endosome 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CYBANCF1NCF2NCF4NFE2L2RAC2TRAF6TRPC3
Complex memberships
TRPC3-Nox2 complexcytochrome b558 / NADPH oxidase (NOX2-p22phox-p47phox-p67phox-p40phox-Rac)

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 gp91(phox) is the sole heme-binding subunit of flavocytochrome b558. COS7 cells expressing gp91(phox) alone showed a b-type cytochrome spectrum identical to neutrophil flavocytochrome b558, with two heme groups at midpoint potentials of -264 and -233 mV. p22(phox) alone showed no heme spectrum. However, coexpression of both subunits was required to reconstitute O2- production with neutrophil cytosol, indicating both subunits are necessary for functional NADPH oxidase assembly. Transgenic COS7 cell expression, spectral analysis, redox titration, confocal microscopy, immunoblotting of subcellular fractions, cell-free superoxide production assay Proceedings of the National Academy of Sciences of the United States of America High 9653128
1995 gp91-phox and p22-phox form a 1:1 stoichiometric heterodimer in cytochrome b558. Direct N-terminal peptide sequencing of affinity-purified cytochrome b558 from human neutrophil membranes yielded a p22-phox:gp91-phox amino acid ratio of 0.96 ± 0.05, consistent with a 1:1 stoichiometry. Affinity purification of cytochrome b558 from neutrophil membranes, direct N-terminal peptide sequencing with quantitative amino acid analysis Biochemistry High 8527449
2008 gp91phox/NOX2 is phosphorylated by protein kinase C (PKC) in stimulated human neutrophils. PKC phosphorylates the cytosolic carboxy-terminal flavoprotein domain of gp91phox on the same peptides phosphorylated in intact cells. PKC phosphorylation enhances the diaphorase activity of the gp91phox flavoprotein domain and increases its binding to Rac2, p67phox, and p47phox, thereby enhancing NADPH oxidase complex assembly and catalytic activity. 2D tryptic peptide mapping, in vitro PKC phosphorylation of recombinant gp91phox cytosolic domain, diaphorase activity assay, binding assays with Rac2/p67phox/p47phox, PKC inhibitor (GF109203X) in intact neutrophils, CGD patient controls FASEB journal High 19028840
2000 Four missense mutations in gp91phox (Cys369Arg, Gly408Glu, Glu568Lys, Thr341Lys) identified in X-CGD patients abolish NADPH oxidase activity. Mutations at residues 369, 408, and 568 strongly impaired translocation/binding of p47phox and p67phox to the membrane cytochrome b558 in stimulated neutrophils and cell-free translocation assay. The Thr341Lys substitution (in the FAD-binding domain) supported normal p47phox/p67phox translocation but abolished electron transfer, implicating this residue in hydride transfer from NADPH to FAD. All four substitutions eliminated electron transfer in solubilized plasma membranes. Site-directed mutagenesis / natural patient mutations, cell-free translocation assay with neutrophil membranes and cytosol, electron transfer assay in solubilized membranes Blood High 10627478
1991 CCAAT displacement protein (CDP) functions as a transcriptional repressor of the gp91-phox (CYBB) gene. CDP binds the CCAAT-containing region of the proximal gp91-phox promoter, displacing CP1, and is present in nuclear extracts of non-expressing cells but absent/reduced in expressing cells. Deletion of the CDP/CP1-binding site from the promoter relieved repression; mutation of the CP1 site alone did not derepress, suggesting CDP represses through additional cis-elements. In vitro DNA-binding assays, nuclear extract analysis from expressing/non-expressing cells, promoter/reporter transfection assays with deletion and point mutations The Journal of biological chemistry High 1885602
1998 IFN-γ-induced transcription of gp91(phox) (CYBB) requires a multiprotein complex (HAF1/HAF1a) containing PU.1, IRF-1, and ICSBP binding to the proximal CYBB promoter. PU.1 with IRF-1 reconstitutes HAF1; PU.1 with all three factors reconstitutes HAF1a. Promoter activation requires serine 148-phosphorylated PU.1. PU.1 + IRF-1 + ICSBP together strongly activate CYBB transcription, much more than any pairwise combination. Electrophoretic mobility shift assay (EMSA), immunoprecipitation/cross-immunoreactivity, in vitro translation/reconstitution, transient co-transfection reporter assays in U937 cells The Journal of biological chemistry High 9593745
2001 SHP1 protein-tyrosine phosphatase inhibits gp91PHOX expression in undifferentiated myeloid cells by decreasing interaction of PU.1, IRF1, ICSBP, and CBP with the CYBB gene promoter. IRF1 and ICSBP are tyrosine-phosphorylated during IFN-γ-induced myeloid differentiation, and specific tyrosine residues in IRF1 and ICSBP are required for CYBB transcription. SHP1 thus antagonizes myeloid differentiation-stage-specific CYBB transcription by dephosphorylating these factors. Reporter gene assays, EMSA, co-immunoprecipitation, phosphorylation site mutagenesis, SHP1 overexpression/knockdown in myeloid cell lines The Journal of biological chemistry Medium 11483597
2002 IFN-γ-induced CYBB transcription is mediated by cooperation of phosphorylated STAT-1α binding to a GAS element at -100 bp and IRF-1 binding to an ISRE at -88 bp of the gp91(phox) promoter. Site-directed mutagenesis of either element reduced IFN-γ-dependent transcription; both elements together are required for full induction. Transient expression assay with truncated/mutated reporters in U937 cells, EMSA with specific antibodies and GAS competitors, site-directed mutagenesis The Journal of biological chemistry High 11781315
1995 A hematopoietic-restricted cis-element in the proximal gp91-phox promoter (around -57 to -52 bp) binds a hematopoiesis-associated factor (HAF1) required for IFN-γ-induced gp91-phox transcription. Single base-pair mutations at -57, -55, -53, and -52 bp that abolish HAF1 binding are found in CGD patients and functionally reduce promoter activity. In vitro DNA-binding assays, promoter/reporter transfection assays, site-directed mutagenesis The Journal of biological chemistry High 7713934
1999 Elf-1 and PU.1 (Ets family transcription factors) bind the -57 to -52 bp element in the gp91(phox) promoter and trans-activate the proximal promoter. CGD mutations at -57 and -55 bp reduce binding affinity of both Elf-1 and PU.1 and diminish transactivation. No synergy was detected when both factors were coexpressed. EMSA, transient co-transfection reporter assays in HeLa and PLB985 cells, CGD mutation analysis Blood Medium 10233904
1999 YY1 binds five cis-elements in the gp91(phox) promoter and trans-activates the promoter in myeloid cells. YY1 antiserum disrupts BID complexes at all four BID-binding sites. Overexpression of YY1 activates a minimal promoter with two copies of the -145 bp binding site. YY1 competes with the repressor CDP for these binding sites during myeloid differentiation. Expression library screen, EMSA with antiserum, transient co-transfection reporter assays The Journal of biological chemistry Medium 10514482
2005 HoxA9 activates CYBB transcription in differentiated myeloid cells via the same promoter cis-element repressed by HoxA10. HoxA9-mediated CYBB transcription requires Pbx1 co-factor and is inhibited by Meis1. Tyrosine phosphorylation of conserved HD residues increases HoxA9 binding to the CYBB promoter. The leukemia-associated Nup98-HoxA9 fusion protein blocks HoxA9-induced CYBB transcription by competing for the cis-element with phosphorylation-independent binding. Reporter gene assays, EMSA, co-immunoprecipitation, overexpression of HoxA9/Nup98-HoxA9/Pbx1/Meis1 in myeloid cell lines, phosphorylation site mutagenesis The Journal of biological chemistry Medium 15681849
2006 SHP2 protein-tyrosine phosphatase dephosphorylates HoxA10, increasing HoxA10 binding to CYBB and NCF2 promoter cis-elements and thereby repressing gp91(PHOX) and p67(PHOX) expression. Constitutively active SHP2 mutants maintain persistent HoxA10-mediated CYBB repression during myelopoiesis, suggesting that activating SHP2 mutations cooperate with HoxA10 overexpression to block myeloid differentiation. Reporter gene assays, EMSA, co-immunoprecipitation, overexpression of SHP2 mutants in myeloid cell lines The Journal of biological chemistry Medium 17138561
2004 JAK2 activation is necessary and sufficient for IFN-γ-induced CYBB transcription in phagocytic cells. JAK2 mediates ICSBP tyrosine phosphorylation (promoting ICSBP interaction with the HAF1 element) and HoxA10 tyrosine phosphorylation (abolishing HoxA10 repression of CYBB). Both events are downstream of JAK2 and together mediate IFN-γ-induced CYBB transcription. JAK2 inhibition/dominant-negative constructs, constitutively active JAK2 expression, EMSA, reporter gene assays in phagocytic cell lines Journal of leukocyte biology Medium 15496449
2000 In coronary microvascular endothelial cells, gp91-phox and p22-phox are predominantly intracellular and colocalized in the vicinity of the endoplasmic reticulum, distinct from their plasma membrane/granule location in neutrophils. The endothelial gp91-phox sequence has differences in a putative NADPH-binding domain and putative glycosylation sites compared with phagocytic gp91-phox. cDNA cloning and sequence analysis, subcellular fractionation with immunoblotting, immunofluorescence colocalization in endothelial cells Arteriosclerosis, thrombosis, and vascular biology Medium 10938010
2006 Nox2 and p22phox interact in endothelial cells as shown by bimolecular fluorescent complementation. NOX2 colocalizes with the ER marker calreticulin and with F-actin at the plasma membrane. NOX2 and NOX4, but not NOX1, contribute equally to endothelial ROS production and proliferation under basal conditions. Bimolecular fluorescent complementation, immunofluorescence colocalization, siRNA knockdown with ROS measurement and proliferation assay Antioxidants & redox signaling Medium 16987004
2006 Nox2-derived ROS from endosomal compartments promote H2O2-dependent recruitment of TRAF6 to the IL-1R1/MyD88 endosomal complex, enabling IKK and NF-κB activation. Rac1 recruits Nox2 into the endosomal compartment independently of MyD88. MyD88-dependent endocytosis of IL-1R1 is required for the redox-dependent formation of the active signaling complex. Scavenging endosomal superoxide or H2O2 significantly abrogated IL-1β-dependent NF-κB activation. siRNA knockdown (Nox2, MyD88, Rac1), endosomal superoxide/H2O2 measurement, co-immunoprecipitation of endosomal complexes, NF-κB/IKK activation assays Molecular and cellular biology High 16354686
2009 NMDA receptor activation generates ROS in postsynaptic neurons through a NOX2-containing NADPH oxidase. The pathway involves nNOS → cGMP → PKG → NOX2 activation. In NOX2-knockout mice, NMDA-induced ROS increase was absent but the cerebral blood flow increase was preserved. Electron microscopy confirmed NOX2 immunolabeling in postsynaptic somata and dendrites co-expressing NMDA NR1 subunit and nNOS. In neuronal cultures, NMDA-induced ROS were blocked by NADPH oxidase inhibitors. In vivo NMDA application with ROS measurement, NOX2 knockout mice, electron microscopy immunolabeling, neuronal cultures with NADPH oxidase inhibitors, cGMP/PKG pathway inhibitors The Journal of neuroscience High 19244529
2017 Nox2 forms a stable physical complex with TRPC3 channels in cardiomyocytes. Doxorubicin increases Nox2 protein levels and promotes TRPC3-Nox2 coupling, driving ROS overproduction and myocardial atrophy. Expression of a TRPC3 C-terminal minipeptide inhibiting TRPC3-Nox2 coupling suppressed doxorubicin-induced atrophy and LV dysfunction in mice. Co-immunoprecipitation (TRPC3-Nox2 complex), cardiomyocyte-specific dominant-negative minipeptide expression, ROS measurement, echocardiography, TRPC3-knockout mice JCI insight High 28768915
2019 In cardiomyocytes, ATP-induced Nox2 upregulation and ROS overproduction mediating atrophy depends on increased physical interaction between Nox2 and TRPC3. Knockdown of either TRPC3 or Nox2 suppressed nutritional deficiency-induced ATP release, ROS production, and cardiomyocyte atrophy, establishing a TRPC3-Nox2 axis as a key mediator. Co-immunoprecipitation, siRNA knockdown of TRPC3 and Nox2, ROS measurement, cardiomyocyte size assay Scientific reports Medium 31278358
2000 In p67-phox-deficient CGD patients, both p67-phox and p40-phox are absent from cytosol. Reconstitution of NADPH oxidase activity requires dissociation of the p40-phox/p67-phox complex; p40-phox acts as a negative regulatory factor stabilizing the resting state by inhibiting p67-phox function. Adding recombinant p40-phox reversed p67-phox-mediated complementation in a dose-dependent manner in cell-free assays. Cell-free NADPH oxidase reconstitution assay with purified cytochrome b558, isolated cytosolic factors, recombinant p67-phox and p40-phox; B-cell line model European journal of biochemistry High 10672014
1996 Retroviral transfer of human gp91phox (MSCV-h91Neo vector) into X-CGD PLB-985 cells fully reconstitutes respiratory burst oxidase activity in the majority of clones. Gene transfer into murine X-CGD bone marrow cells restored respiratory burst activity in granulocyte-monocyte progeny differentiated in vitro, demonstrating functional complementation of the enzymatic defect. Retroviral gene transfer, DHR/oxidative burst assay, Western blotting for gp91phox expression, in vitro granulocyte differentiation of murine bone marrow Blood Medium 8781441
1996 In X-CGD B-cell lines, mutations in gp91-phox lead to accumulation of an incompletely glycosylated gp91-phox precursor, similar to what is seen when p22-phox is absent. The affected mutations mapped to the FAD-binding domain, a potential heme-binding domain, and the region encoded by exon 3, delineating regions of gp91-phox important for biosynthesis and stable association with p22-phox. Western blotting of B-cell line lysates, identification of gp91-phox precursor species, mutation mapping The Biochemical journal Medium 8615831
2017 NOX2 (gp91phox) activity is down-regulated by ATM kinase-dependent phosphorylation at Ser486 within the NOX2 insertion sequence (NIS). PMA stimulation triggers Ser486 phosphorylation in purified cytochrome b558. ATM inhibition or Ser486Ala mutation enhanced NOX2 activity, while Ser486Glu mutation inhibited it. Deletion or exchange of NIS abolished both NADPH oxidase and reductase activity and impaired p47phox/p67phox phagosomal translocation. NOX2 chimera construction (NIS deletion/exchange), functional oxidase and reductase activity assays in PLB-985 cells, mass spectrometry phosphorylation mapping, ATM kinase inhibitor, Ser486Ala/Glu point mutations Free radical biology & medicine High 28916473
2021 NOX2 oxidative burst results from a Rac-dependent feedforward autoactivation mechanism. Active Rac triggers NOX2 to produce O2-, which in turn activates redox-sensitive Rac, further activating NOX2 in a positive feedback loop. Mutagenesis-based kinetic analyses showed enzymatic Rac activation initiates the cycle, while redox-mediated Rac activation drives ~98% of NOX2 activation and accounts for the characteristic burst kinetics. Mutagenesis of Rac redox-sensitive residues, kinetic O2- production assays, cell-based ROS measurements, NOX2 reconstitution assays The Journal of biological chemistry High 34293347
2016 Nox2 activation promotes thioredoxin-1 (TRX-1)/p40phox interaction in the cytosol, leading to nuclear exclusion of TRX-1. Conversely, genetic Nox2 deficiency or apocynin inhibition causes reductive stress with nuclear TRX-1 accumulation and NF-κB hyperactivation after LPS stimulation. This identifies a Nox2/TRX-1/NF-κB signaling pathway relevant to CGD-associated hyperinflammation. Co-immunoprecipitation (TRX-1/p40phox), nuclear fractionation, NF-κB reporter, Nox2 KO mice, apocynin pharmacology, primary CGD patient monocytes/neutrophils, TrxR-1 inhibitors Scientific reports Medium 27698473
2016 NOX2/gp91phox contributes to RANKL-induced osteoclast differentiation by upregulating NFATc1. Mice deficient in gp91phox showed ~30% reduction in osteoclast differentiation, increased bone density, and impaired RANKL-induced NFATc1 expression. H2O2 treatment almost completely rescued osteoclast differentiation in gp91phox-/- bone marrow monocytes, establishing superoxide as a signaling intermediate upstream of NFATc1. gp91phox knockout mice, in vitro osteoclast differentiation assay, H2O2 rescue experiment, antioxidant/superoxide inhibitor treatment of wild-type BMMs, NFATc1 expression analysis Scientific reports Medium 27897222
2014 Lipid (palmitate)-induced Nox2 activation via PKCβII impairs lysosomal acidification and enzyme activity in cardiomyocytes through superoxide production, blocking autophagic flux. Inhibition of Nox2 prevented superoxide overproduction, restored lysosomal pH and enzyme activity, and reduced autophagosome accumulation. Nox2 siRNA knockdown and pharmacological inhibition in H9C2 cells, lysosomal pH measurement, lysosomal enzyme activity assay, PKCβII inhibitors, in vivo high-fat feeding model Journal of lipid research Medium 25529920
2019 NOX2 suppression in leukemic stem cells (LSCs) collapses the self-renewal transcriptional program and activates myeloid differentiation programs. Downstream of NOX2, the forkhead transcription factor FOXC1 mediates this phenotype. Suppression of either NOX2 or FOXC1 induced differentiation of leukemic blasts and attenuated disease in xenotransplantation models of primary human myeloid leukemia. NOX2 knockout/knockdown in murine leukemia model, transcriptional analysis of purified LSCs, FOXC1 knockdown, xenotransplantation with primary human leukemia cells Cell reports Medium 30943405
2020 CYBB/NOX2 in conventional dendritic cells (cDCs) regulates LC3-associated phagocytosis (LAP) of MOG antigen and supports MOG-antigen presentation to CD4+ T cells via MHC class II. Genetic ablation of Cybb specifically in cDCs reduced encephalitogenic TH cell recruitment into the CNS and ameliorated EAE upon adoptive transfer of MOG-specific CD4+ T cells, placing CYBB in the LAP-dependent antigen processing pathway. Conditional Cybb deletion in cDCs (cDC-specific Cybb KO), EAE adoptive transfer model, antigen presentation assay, LAP analysis Autophagy Medium 32401602
2018 CYBB/NOX2 in glioblastoma cells interacts with Nrf2 and thereby regulates SOD2 transcription. TMZ-resistant GBM cells displayed CYBB/Nrf2/SOD2 axis activation maintaining high ROS state while conferring ferroptosis resistance. CYBB knockdown reduced erastin-mediated ferroptosis resistance in TMZ-resistant cells. Co-immunoprecipitation (CYBB-Nrf2), SOD2 expression after CYBB knockdown/overexpression, erastin ferroptosis assay, xenograft mouse model International journal of molecular sciences Medium 37175412
2016 Nox2-derived ROS mediate macrophage macropinocytosis via PI3K/Akt pathway and cofilin activation. PKC-dependent Nox2 activation generates intracellular superoxide that inhibits PTEN, activates PI3K/Akt, and activates cofilin-mediated actin reorganization promoting membrane ruffling and macropinosome formation. In vivo peritoneal chimera experiments showed reduced macropinocytotic lipid uptake in Nox2-deficient macrophages in hypercholesterolemic ApoE-/- mice. Nox2 siRNA knockdown, PKC inhibitors, intracellular superoxide scavenging, PI3K/Akt/cofilin activation assays, peritoneal chimera with Nox2y/- macrophages in ApoE-/- mice Antioxidants & redox signaling Medium 27488058
2019 In zebrafish nox2/cybb mutants, retinal ganglion cell axons are mistargeted in the optic tectum and the ganglion cell layer is expanded, establishing a cell-autonomous role for Nox2/Cybb in retinotectal axonal connectivity and optic nerve formation. CRISPR/Cas9-generated nox2/cybb zebrafish mutants (chimeric and homozygous), pan-Nox inhibitor (celastrol) treatment, H2O2 rescue, cultured retinal ganglion cell neurite outgrowth assay with Nox inhibitors The Journal of neuroscience Medium 29793976
2021 TAZ transcriptionally induces Cybb (encoding NOX2) in hepatocytes. Elevated NOX2 activity leads to NADPH oxidase-mediated oxidative DNA damage that promotes hepatocellular carcinoma development in NASH. shRNA silencing of Cybb or overexpression of DNA-repair enzymes (OGG1, NHEJ1) suppressed tumor formation in pre-tumor NASH mice. Correlation between TAZ, NOX2, and oxidative DNA damage was confirmed in human NASH-HCC non-tumor liver tissue. AAV8-H1-shCybb gene silencing in pre-tumor NASH mice, AAV8-TBG-OGG1/NHEJ1 rescue, 8-oxoguanine/DNA damage assays, transcriptional analysis Journal of hepatology Medium 34902531
2003 Neutrophil gp91phox-derived superoxide is the principal mechanism by which neutrophils cause muscle membrane lysis in vitro and in vivo. gp91phox null neutrophils failed to produce superoxide and caused significantly less muscle cell cytolysis in vitro. In vivo hindlimb reloading of gp91phox null mice showed 90% reduction in muscle fibre membrane injury despite unchanged neutrophil/macrophage infiltration. gp91phox null mutant mice, in vitro cytotoxicity assay (neutrophils vs. muscle cells), in vivo muscle reloading model with membrane lesion quantification (extracellular dye uptake), leukocyte counting The Journal of physiology High 14555723
2017 Targeted repair of CYBB exon 5 mutations by TALEN or Cas9-mediated exon replacement in X-CGD iPSCs restored gp91phox expression and ROS production in iPSC-derived granulocytes. Insertion of an exon 1-13 minigene at exon 1 failed to restore gp91phox expression, whereas insertion of an exon 2-13 minigene at exon 2 fully restored gp91phox and ROS activity. This demonstrated that intronic sequences in intron 1 are necessary for CYBB expression from the endogenous locus. TALEN and Cas9 gene editing in patient iPSCs, iPSC differentiation to granulocytes, gp91phox Western blot, oxidative burst/ROS assay Molecular therapy Medium 28153086

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Novel gp91(phox) homologues in vascular smooth muscle cells : nox1 mediates angiotensin II-induced superoxide formation and redox-sensitive signaling pathways. Circulation research 720 11348997
2001 Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5. Gene 681 11376945
2003 Nicotiana benthamiana gp91phox homologs NbrbohA and NbrbohB participate in H2O2 accumulation and resistance to Phytophthora infestans. The Plant cell 411 12615943
2009 p47phox, the phagocyte NADPH oxidase/NOX2 organizer: structure, phosphorylation and implication in diseases. Experimental & molecular medicine 349 19372727
2005 Expression and localization of NOX2 and NOX4 in primary human endothelial cells. Antioxidants & redox signaling 272 15706079
2019 A TAZ-ANGPTL4-NOX2 Axis Regulates Ferroptotic Cell Death and Chemoresistance in Epithelial Ovarian Cancer. Molecular cancer research : MCR 262 31641008
1991 CCAAT displacement protein as a repressor of the myelomonocytic-specific gp91-phox gene promoter. The Journal of biological chemistry 234 1885602
2004 gp91phox-containing NADPH oxidase mediates endothelial dysfunction in renovascular hypertension. Circulation 211 15037533
2009 NMDA receptor activation increases free radical production through nitric oxide and NOX2. The Journal of neuroscience : the official journal of the Society for Neuroscience 207 19244529
2006 NOX2 and NOX4 mediate proliferative response in endothelial cells. Antioxidants & redox signaling 207 16987004
2000 Molecular characterization and localization of the NAD(P)H oxidase components gp91-phox and p22-phox in endothelial cells. Arteriosclerosis, thrombosis, and vascular biology 204 10938010
2006 Nox2 and Rac1 regulate H2O2-dependent recruitment of TRAF6 to endosomal interleukin-1 receptor complexes. Molecular and cellular biology 192 16354686
1998 Gp91(phox) is the heme binding subunit of the superoxide-generating NADPH oxidase. Proceedings of the National Academy of Sciences of the United States of America 174 9653128
2016 NOX2-dependent regulation of inflammation. Clinical science (London, England : 1979) 173 26888560
2011 The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice. Hepatology (Baltimore, Md.) 172 21384410
2011 NOX2 complex-derived ROS as immune regulators. Antioxidants & redox signaling 161 20919938
2010 Gp91phox (NOX2) in classically activated microglia exacerbates traumatic brain injury. Journal of neuroinflammation 157 20659322
2000 Upregulation of p67(phox) and gp91(phox) in aortas from angiotensin II-infused mice. American journal of physiology. Heart and circulatory physiology 151 11045958
2019 The phagocyte NOX2 NADPH oxidase in microbial killing and cell signaling. Current opinion in immunology 147 31302569
2008 Regulation of the phagocyte NADPH oxidase activity: phosphorylation of gp91phox/NOX2 by protein kinase C enhances its diaphorase activity and binding to Rac2, p67phox, and p47phox. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 139 19028840
1998 PU.1, interferon regulatory factor 1, and interferon consensus sequence-binding protein cooperate to increase gp91(phox) expression. The Journal of biological chemistry 139 9593745
2020 Nox2 activation in Covid-19. Redox biology 122 32738789
2000 NADPH oxidase subunit, gp91(phox) homologue, preferentially expressed in human colon epithelial cells. Gene 122 10974555
2001 Induction of plant gp91 phox homolog by fungal cell wall, arachidonic acid, and salicylic acid in potato. Molecular plant-microbe interactions : MPMI 117 11386368
2009 Hereditary deficiency of gp91(phox) is associated with enhanced arterial dilatation: results of a multicenter study. Circulation 114 19805647
2014 Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity. Journal of lipid research 113 25529920
2001 Expression of p22-phox and gp91-phox, essential components of NADPH oxidase, increases after myocardial infarction. Biochemical and biophysical research communications 100 11243862
2008 Inflammatory manifestations in chronic granulomatous disease (CGD). Journal of clinical immunology 97 18193341
2021 Nox2 impairs VEGF-A-induced angiogenesis in placenta via mitochondrial ROS-STAT3 pathway. Redox biology 96 34217063
2005 The Candida Genome Database (CGD), a community resource for Candida albicans gene and protein information. Nucleic acids research 95 15608216
2002 Increased NADPH oxidase activity, gp91phox expression, and endothelium-dependent vasorelaxation during neointima formation in rabbits. Circulation research 80 12114322
2019 The Hematopoietic Oxidase NOX2 Regulates Self-Renewal of Leukemic Stem Cells. Cell reports 71 30943405
2023 Unlocking the power of NOX2: A comprehensive review on its role in immune regulation. Redox biology 67 37379662
2003 L-arginine reverses p47phox and gp91phox expression induced by high salt in Dahl rats. Hypertension (Dallas, Tex. : 1979) 66 14504257
2002 Cooperation of STAT-1 and IRF-1 in interferon-gamma-induced transcription of the gp91(phox) gene. The Journal of biological chemistry 65 11781315
2012 The HIF1 target gene NOX2 promotes angiogenesis through urotensin-II. Journal of cell science 61 22399808
2017 TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy. JCI insight 59 28768915
2011 Inflammation and repeated infections in CGD: two sides of a coin. Cellular and molecular life sciences : CMLS 59 22083605
2005 HOXA9 activates transcription of the gene encoding gp91Phox during myeloid differentiation. The Journal of biological chemistry 59 15681849
2016 TSPO Finds NOX2 in Microglia for Redox Homeostasis. Trends in pharmacological sciences 58 27113160
2016 NADPH oxidase gp91phox contributes to RANKL-induced osteoclast differentiation by upregulating NFATc1. Scientific reports 57 27897222
2003 Null mutation of gp91phox reduces muscle membrane lysis during muscle inflammation in mice. The Journal of physiology 57 14555723
2018 NOX2 in autoimmunity, tumor growth and metastasis. The Journal of pathology 55 30270440
2000 Complementation of NADPH oxidase in p67-phox-deficient CGD patients p67-phox/p40-phox interaction. European journal of biochemistry 55 10672014
2018 Association of NOX2 subunits genetic variants with autoimmune diseases. Free radical biology & medicine 53 29526808
2001 SHP1 protein-tyrosine phosphatase inhibits gp91PHOX and p67PHOX expression by inhibiting interaction of PU.1, IRF1, interferon consensus sequence-binding protein, and CREB-binding protein with homologous Cis elements in the CYBB and NCF2 genes. The Journal of biological chemistry 53 11483597
2014 Loss of NOX2 (gp91phox) prevents oxidative stress and progression to advanced heart failure. Clinical science (London, England : 1979) 52 24624929
2000 Statistical and mutational analysis of chronic granulomatous disease in Japan with special reference to gp91-phox and p22-phox deficiency. Human genetics 52 10914676
2020 NOX2-Derived Reactive Oxygen Species in Cancer. Oxidative medicine and cellular longevity 49 33312338
2020 CYBB/NOX2 in conventional DCs controls T cell encephalitogenicity during neuroinflammation. Autophagy 48 32401602
2013 Contribution of iNOS/sGC/PKG pathway, COX-2, CYP4A1, and gp91(phox) to the protective effect of 5,14-HEDGE, a 20-HETE mimetic, against vasodilation, hypotension, tachycardia, and inflammation in a rat model of septic shock. Nitric oxide : biology and chemistry 48 23684565
2011 Gp91(phox) contributes to the development of experimental inflammatory bowel disease. Immunology and cell biology 48 21321580
2017 Targeted Repair of CYBB in X-CGD iPSCs Requires Retention of Intronic Sequences for Expression and Functional Correction. Molecular therapy : the journal of the American Society of Gene Therapy 46 28153086
1995 Stoichiometry of p22-phox and gp91-phox in phagocyte cytochrome b558. Biochemistry 45 8527449
2023 Activation of neuronal NADPH oxidase NOX2 promotes inflammatory neurodegeneration. Free radical biology & medicine 44 36870375
1996 High-level reconstitution of respiratory burst activity in a human X-linked chronic granulomatous disease (X-CGD) cell line and correction of murine X-CGD bone marrow cells by retroviral-mediated gene transfer of human gp91phox. Blood 44 8781441
2021 Correction of X-CGD patient HSPCs by targeted CYBB cDNA insertion using CRISPR/Cas9 with 53BP1 inhibition for enhanced homology-directed repair. Gene therapy 43 33712802
2017 Nox2 contributes to hyperinsulinemia-induced redox imbalance and impaired vascular function. Redox biology 43 28600985
1995 Characterization of a gp91-phox promoter element that is required for interferon gamma-induced transcription. The Journal of biological chemistry 42 7713934
2023 NADPH Oxidase Subunit CYBB Confers Chemotherapy and Ferroptosis Resistance in Mesenchymal Glioblastoma via Nrf2/SOD2 Modulation. International journal of molecular sciences 40 37175412
2016 Apocynin and Nox2 regulate NF-κB by modifying thioredoxin-1 redox-state. Scientific reports 40 27698473
2021 TAZ-induced Cybb contributes to liver tumor formation in non-alcoholic steatohepatitis. Journal of hepatology 37 34902531
2015 Nox2 is a mediator of ischemia reperfusion injury. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 37 26104383
2023 Metformin inhibits ovarian granular cell pyroptosis through the miR-670-3p/NOX2/ROS pathway. Aging 36 37244286
2011 Prodigiosin inhibits gp91(phox) and iNOS expression to protect mice against the oxidative/nitrosative brain injury induced by hypoxia-ischemia. Toxicology and applied pharmacology 36 21925195
2006 Activation of SHP2 protein-tyrosine phosphatase increases HoxA10-induced repression of the genes encoding gp91(PHOX) and p67(PHOX). The Journal of biological chemistry 36 17138561
2024 Nox2 inhibition reduces trophoblast ferroptosis in preeclampsia via the STAT3/GPX4 pathway. Life sciences 35 38460811
2020 Nobiletin alleviates high-fat diet-induced nonalcoholic fatty liver disease by modulating AdipoR1 and gp91phox expression in rats. The Journal of nutritional biochemistry 35 33096235
2014 Primary immunodeficiency caused by an exonized retroposed gene copy inserted in the CYBB gene. Human mutation 35 24478191
2000 Four novel mutations in the gene encoding gp91-phox of human NADPH oxidase: consequences for oxidase assembly. Blood 35 10627478
2019 Nox2-dependent Neuroinflammation in An EAE Model of Multiple Sclerosis. Translational neuroscience 33 30984416
1999 Elf-1 and PU.1 induce expression of gp91(phox) via a promoter element mutated in a subset of chronic granulomatous disease patients. Blood 32 10233904
2023 Complement C3 Enhances LPS-Elicited Neuroinflammation and Neurodegeneration Via the Mac1/NOX2 Pathway. Molecular neurobiology 31 37268807
2019 Liraglutide prevents β-cell apoptosis via inactivation of NOX2 and its related signaling pathway. Journal of diabetes and its complications 30 30772113
2018 Pulmonary metastatic colonisation and granulomas in NOX2-deficient mice. The Journal of pathology 30 30062795
2023 Chronic Granulomatous Disease (CGD): Commonly Associated Pathogens, Diagnosis and Treatment. Microorganisms 29 37764077
2006 Superoxide auto-augments superoxide formation and upregulates gp91(phox) expression in porcine pulmonary artery endothelial cells: inhibition by iloprost. European journal of pharmacology 29 16647052
1999 YY1 binds five cis-elements and trans-activates the myeloid cell-restricted gp91(phox) promoter. The Journal of biological chemistry 29 10514482
2005 Expression of NOX-I, gp91phox, p47phox and P67phox in the aorta segments above and below coarctation. Biochimica et biophysica acta 28 15814300
2012 Alpharetroviral vector-mediated gene therapy for X-CGD: functional correction and lack of aberrant splicing. Molecular therapy : the journal of the American Society of Gene Therapy 27 23207695
2019 TRPC3-Nox2 axis mediates nutritional deficiency-induced cardiomyocyte atrophy. Scientific reports 26 31278358
1996 Detection of gp91-phox precursor protein in B-cell lines from patients with X-linked chronic granulomatous disease as an indicator for mutations impairing cytochrome b558 biosynthesis. The Biochemical journal 26 8615831
2023 Activated SIRT1 contributes to DPT-induced glioma cell parthanatos by upregulation of NOX2 and NAT10. Acta pharmacologica Sinica 25 37277492
2023 Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD. Blood 25 37562003
2018 NOX2 oxidase expressed in endosomes promotes cell proliferation and prostate tumour development. Oncotarget 25 30459931
2019 Nox2 Regulates Platelet Activation and NET Formation in the Lung. Frontiers in immunology 24 31338092
2015 A NOX2/Egr-1/Fyn pathway delineates new targets for TKI-resistant malignancies. Oncotarget 24 26136341
2004 JAK2 is necessary and sufficient for interferon-gamma-induced transcription of the gene encoding gp91PHOX. Journal of leukocyte biology 24 15496449
2018 Inhibition of phosphodiesterase 2 reverses gp91phox oxidase-mediated depression- and anxiety-like behavior. Neuropharmacology 23 30268520
2016 Nox2-Mediated PI3K and Cofilin Activation Confers Alternate Redox Control of Macrophage Pinocytosis. Antioxidants & redox signaling 23 27488058
2024 Microglial gp91phox-mediated neuroinflammation and ferroptosis contributes to learning and memory deficits in rotenone-treated mice. Free radical biology & medicine 22 38697489
2021 Rac-dependent feedforward autoactivation of NOX2 leads to oxidative burst. The Journal of biological chemistry 22 34293347
2019 NOX2 mediates quiescent handling of dead cell remnants in phagocytes. Redox biology 22 31349119
2017 Down-regulation of NOX2 activity in phagocytes mediated by ATM-kinase dependent phosphorylation. Free radical biology & medicine 22 28916473
2014 Equol is neuroprotective during focal cerebral ischemia and reperfusion that involves p-Src and gp91(phox). Current neurovascular research 22 25198009
2024 Spinal AT1R contributes to neuroinflammation and neuropathic pain via NOX2-dependent redox signaling in microglia. Free radical biology & medicine 21 39638264
2013 Nox2 and Nox4 influence neonatal c-kit(+) cardiac precursor cell status and differentiation. American journal of physiology. Heart and circulatory physiology 21 23832701
2002 CYBB mutation analysis in X-linked chronic granulomatous disease. Clinical immunology (Orlando, Fla.) 21 12139950
2018 nox2/cybb Deficiency Affects Zebrafish Retinotectal Connectivity. The Journal of neuroscience : the official journal of the Society for Neuroscience 20 29793976
2017 NOX2-dependent immunosuppression in chronic myelomonocytic leukemia. Journal of leukocyte biology 20 28292946

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