ID NOX4_HUMAN Reviewed; 578 AA. AC Q9NPH5; A8K715; B7Z520; E7EMD7; Q5K3R4; Q5K3R5; Q5K3R6; Q5K3R8; Q7Z7G3; AC Q86V92; DT 30-MAY-2006, integrated into UniProtKB/Swiss-Prot. DT 04-NOV-2008, sequence version 2. DT 27-MAR-2024, entry version 174. DE RecName: Full=NADPH oxidase 4; DE EC=1.6.3.1 {ECO:0000269|PubMed:14966267, ECO:0000269|PubMed:15356101, ECO:0000269|PubMed:15927447, ECO:0000269|PubMed:21343298, ECO:0000269|PubMed:25062272}; DE AltName: Full=Kidney oxidase-1; DE Short=KOX-1; DE AltName: Full=Kidney superoxide-producing NADPH oxidase; DE AltName: Full=Renal NAD(P)H-oxidase; GN Name=NOX4; Synonyms=RENOX; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), DEVELOPMENTAL STAGE, VARIANT RP ILE-315, FUNCTION, AND CATALYTIC ACTIVITY. RC TISSUE=Kidney; RX PubMed=10869423; DOI=10.1073/pnas.130135897; RA Geiszt M., Kopp J.B., Varnai P., Leto T.L.; RT "Identification of renox, an NAD(P)H oxidase in kidney."; RL Proc. Natl. Acad. Sci. U.S.A. 97:8010-8014(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, DEVELOPMENTAL RP STAGE, AND VARIANT ILE-315. RC TISSUE=Fetal kidney; RX PubMed=11376945; DOI=10.1016/s0378-1119(01)00449-8; RA Cheng G., Cao Z., Xu X., van Meir E.G., Lambeth J.D.; RT "Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and RT Nox5."; RL Gene 269:131-140(2001). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, RP DEVELOPMENTAL STAGE, VARIANT ILE-315, AND CATALYTIC ACTIVITY. RC TISSUE=Kidney; RX PubMed=11032835; DOI=10.1074/jbc.m007597200; RA Shiose A., Kuroda J., Tsuruya K., Hirai M., Hirakata H., Naito S., RA Hattori M., Sakaki Y., Sumimoto H.; RT "A novel superoxide-producing NAD(P)H oxidase in kidney."; RL J. Biol. Chem. 276:1417-1423(2001). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 6), TISSUE SPECIFICITY, AND VARIANT RP ILE-315. RX PubMed=15210697; DOI=10.1074/jbc.m404983200; RA Schwarzer C., Machen T.E., Illek B., Fischer H.; RT "NADPH oxidase-dependent acid production in airway epithelial cells."; RL J. Biol. Chem. 279:36454-36461(2004). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3; 4; 5 AND 6), FUNCTION (ISOFORMS 3 RP AND 4), SUBCELLULAR LOCATION, GLYCOSYLATION, VARIANT ILE-315, AND CATALYTIC RP ACTIVITY (ISOFORM 4). RC TISSUE=Lung; RX PubMed=15721269; DOI=10.1016/j.bbrc.2005.01.089; RA Goyal P., Weissmann N., Rose F., Grimminger F., Schaefers H.J., Seeger W., RA Haenze J.; RT "Identification of novel Nox4 splice variants with impact on ROS levels in RT A549 cells."; RL Biochem. Biophys. Res. Commun. 329:32-39(2005). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 6 AND 9), AND VARIANT RP ILE-315. RC TISSUE=Pulmonary artery; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16554811; DOI=10.1038/nature04632; RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G., RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., RA Hattori M., Rogers J., Lander E.S., Sakaki Y.; RT "Human chromosome 11 DNA sequence and analysis including novel gene RT identification."; RL Nature 440:497-500(2006). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 7), AND VARIANT RP ILE-315. RC TISSUE=Ovary; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=15155719; DOI=10.1074/jbc.m400078200; RA Vaquero E.C., Edderkaoui M., Pandol S.J., Gukovsky I., Gukovskaya A.S.; RT "Reactive oxygen species produced by NAD(P)H oxidase inhibit apoptosis in RT pancreatic cancer cells."; RL J. Biol. Chem. 279:34643-34654(2004). RN [10] RP FUNCTION, INTERACTION WITH TLR4, AND CATALYTIC ACTIVITY. RX PubMed=15356101; DOI=10.4049/jimmunol.173.6.3589; RA Park H.S., Jung H.Y., Park E.Y., Kim J., Lee W.J., Bae Y.S.; RT "Direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for RT lipopolysaccharide-induced production of reactive oxygen species and RT activation of NF-kappa B."; RL J. Immunol. 173:3589-3593(2004). RN [11] RP FUNCTION, ACTIVITY REGULATION, AND CATALYTIC ACTIVITY. RX PubMed=14966267; DOI=10.1128/mcb.24.5.1844-1854.2004; RA Mahadev K., Motoshima H., Wu X., Ruddy J.M., Arnold R.S., Cheng G., RA Lambeth J.D., Goldstein B.J.; RT "The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation RT of H2O2 and plays an integral role in insulin signal transduction."; RL Mol. Cell. Biol. 24:1844-1854(2004). RN [12] RP FUNCTION, INDUCTION, SUBCELLULAR LOCATION, ACTIVITY REGULATION, AND RP CATALYTIC ACTIVITY. RX PubMed=15572675; DOI=10.1128/mcb.24.24.10703-10717.2004; RA Pedruzzi E., Guichard C., Ollivier V., Driss F., Fay M., Prunet C., RA Marie J.-C., Pouzet C., Samadi M., Elbim C., O'dowd Y., Bens M., RA Vandewalle A., Gougerot-Pocidalo M.-A., Lizard G., Ogier-Denis E.; RT "NAD(P)H oxidase Nox-4 mediates 7-ketocholesterol-induced endoplasmic RT reticulum stress and apoptosis in human aortic smooth muscle cells."; RL Mol. Cell. Biol. 24:10703-10717(2004). RN [13] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=16230378; DOI=10.1158/0008-5472.can-05-2105; RA Maranchie J.K., Zhan Y.; RT "Nox4 is critical for hypoxia-inducible factor 2-alpha transcriptional RT activity in von Hippel-Lindau-deficient renal cell carcinoma."; RL Cancer Res. 65:9190-9193(2005). RN [14] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=16179589; DOI=10.1161/01.res.0000187457.24338.3d; RA Cucoranu I., Clempus R., Dikalova A., Phelan P.J., Ariyan S., Dikalov S., RA Sorescu D.; RT "NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced RT differentiation of cardiac fibroblasts into myofibroblasts."; RL Circ. Res. 97:900-907(2005). RN [15] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, ACTIVITY REGULATION, RP AND CATALYTIC ACTIVITY. RX PubMed=16324151; DOI=10.1111/j.1365-2443.2005.00907.x; RA Kuroda J., Nakagawa K., Yamasaki T., Nakamura K., Takeya R., RA Kuribayashi F., Imajoh-Ohmi S., Igarashi K., Shibata Y., Sueishi K., RA Sumimoto H.; RT "The superoxide-producing NAD(P)H oxidase Nox4 in the nucleus of human RT vascular endothelial cells."; RL Genes Cells 10:1139-1151(2005). RN [16] RP FUNCTION, INTERACTION WITH CYBA, SUBCELLULAR LOCATION, MUTAGENESIS OF RP ARG-304 AND 575-GLU--SER-578, AND CATALYTIC ACTIVITY. RX PubMed=15927447; DOI=10.1016/j.cellsig.2005.03.023; RA Martyn K.D., Frederick L.M., von Loehneysen K., Dinauer M.C., Knaus U.G.; RT "Functional analysis of Nox4 reveals unique characteristics compared to RT other NADPH oxidases."; RL Cell. Signal. 18:69-82(2006). RN [17] RP FUNCTION, SUBCELLULAR LOCATION, ACTIVITY REGULATION, AND CATALYTIC RP ACTIVITY. RX PubMed=16019190; DOI=10.1016/j.cellsig.2005.05.025; RA Lee Y.-M., Kim B.-J., Chun Y.-S., So I., Choi H., Kim M.-S., Park J.-W.; RT "NOX4 as an oxygen sensor to regulate TASK-1 activity."; RL Cell. Signal. 18:499-507(2006). RN [18] RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, MUTAGENESIS OF HIS-16; RP HIS-47; 218-ASN--GLN-235; HIS-222; CYS-226; HIS-246; HIS-248; RP 264-HIS--GLU-273 AND CYS-270, AND REGION. RX PubMed=21343298; DOI=10.1074/jbc.m110.192138; RA Takac I., Schroeder K., Zhang L., Lardy B., Anilkumar N., Lambeth J.D., RA Shah A.M., Morel F., Brandes R.P.; RT "The E-loop is involved in hydrogen peroxide formation by the NADPH oxidase RT Nox4."; RL J. Biol. Chem. 286:13304-13313(2011). RN [19] RP FUNCTION (ISOFORM 4), SUBCELLULAR LOCATION (ISOFORM 4), AND CATALYTIC RP ACTIVITY (ISOFORM 4). RX PubMed=23393389; DOI=10.1161/atvbaha.112.300956; RA Anilkumar N., San Jose G., Sawyer I., Santos C.X., Sand C., Brewer A.C., RA Warren D., Shah A.M.; RT "A 28-kDa splice variant of NADPH oxidase-4 is nuclear-localized and RT involved in redox signaling in vascular cells."; RL Arterioscler. Thromb. Vasc. Biol. 33:E104-E112(2013). RN [20] RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF HIS-222, AND COFACTOR. RX PubMed=25062272; DOI=10.1021/bi500331y; RA Nisimoto Y., Diebold B.A., Cosentino-Gomes D., Lambeth J.D.; RT "Nox4: a hydrogen peroxide-generating oxygen sensor."; RL Biochemistry 53:5111-5120(2014). RN [21] RP INTERACTION WITH PPP1R15A, AND SUBCELLULAR LOCATION. RX PubMed=26742780; DOI=10.15252/embj.201592394; RA Santos C.X., Hafstad A.D., Beretta M., Zhang M., Molenaar C., Kopec J., RA Fotinou D., Murray T.V., Cobb A.M., Martin D., Zeh Silva M., Anilkumar N., RA Schroeder K., Shanahan C.M., Brewer A.C., Brandes R.P., Blanc E., RA Parsons M., Belousov V., Cammack R., Hider R.C., Steiner R.A., Shah A.M.; RT "Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates RT eIF2alpha-mediated stress signaling."; RL EMBO J. 35:319-334(2016). CC -!- FUNCTION: NADPH oxidase that catalyzes predominantly the reduction of CC oxygen to H2O2 (PubMed:15356101, PubMed:14966267, PubMed:15927447, CC PubMed:25062272, PubMed:21343298). Can also catalyze to a smaller CC extent, the reduction of oxygen to superoxide (PubMed:10869423, CC PubMed:11032835, PubMed:15155719, PubMed:15572675, PubMed:16230378, CC PubMed:16179589, PubMed:16324151, PubMed:15927447, PubMed:16019190, CC PubMed:25062272). May function as an oxygen sensor regulating the CC KCNK3/TASK-1 potassium channel and HIF1A activity (PubMed:16019190). CC May regulate insulin signaling cascade (PubMed:14966267). May play a CC role in apoptosis, bone resorption and lipolysaccharide-mediated CC activation of NFKB (PubMed:15572675, PubMed:15356101). May produce CC superoxide in the nucleus and play a role in regulating gene expression CC upon cell stimulation (PubMed:16324151). {ECO:0000269|PubMed:10869423, CC ECO:0000269|PubMed:11032835, ECO:0000269|PubMed:14966267, CC ECO:0000269|PubMed:15155719, ECO:0000269|PubMed:15356101, CC ECO:0000269|PubMed:15572675, ECO:0000269|PubMed:15927447, CC ECO:0000269|PubMed:16019190, ECO:0000269|PubMed:16179589, CC ECO:0000269|PubMed:16230378, ECO:0000269|PubMed:16324151, CC ECO:0000269|PubMed:21343298, ECO:0000269|PubMed:25062272}. CC -!- FUNCTION: [Isoform 4]: NADPH oxidase that catalyzes the generation of CC superoxide from molecular oxygen utilizing NADPH as an electron donor CC (PubMed:15721269, PubMed:23393389). Involved in redox signaling in CC vascular cells (PubMed:23393389). Modulates the nuclear activation of CC ERK1/2 and the ELK1 transcription factor, and is capable of inducing CC nuclear DNA damage (PubMed:23393389). {ECO:0000269|PubMed:15721269, CC ECO:0000269|PubMed:23393389}. CC -!- FUNCTION: [Isoform 3]: Lacks superoxide-generating NADPH oxidase CC activity. {ECO:0000269|PubMed:15721269}. CC -!- CATALYTIC ACTIVITY: CC Reaction=NADPH + 2 O2 = H(+) + NADP(+) + 2 superoxide; CC Xref=Rhea:RHEA:63180, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, CC ChEBI:CHEBI:18421, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; CC Evidence={ECO:0000269|PubMed:10869423, ECO:0000269|PubMed:11032835, CC ECO:0000269|PubMed:15155719, ECO:0000269|PubMed:15572675, CC ECO:0000269|PubMed:15927447, ECO:0000269|PubMed:16019190, CC ECO:0000269|PubMed:16179589, ECO:0000269|PubMed:16230378, CC ECO:0000269|PubMed:16324151, ECO:0000269|PubMed:25062272}; CC -!- CATALYTIC ACTIVITY: [Isoform 4]: CC Reaction=NADPH + 2 O2 = H(+) + NADP(+) + 2 superoxide; CC Xref=Rhea:RHEA:63180, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, CC ChEBI:CHEBI:18421, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; CC Evidence={ECO:0000269|PubMed:15721269, ECO:0000269|PubMed:23393389}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+) + NADPH + O2 = H2O2 + NADP(+); Xref=Rhea:RHEA:11260, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:16240, CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.6.3.1; CC Evidence={ECO:0000269|PubMed:14966267, ECO:0000269|PubMed:15356101, CC ECO:0000269|PubMed:15927447, ECO:0000269|PubMed:21343298, CC ECO:0000269|PubMed:25062272}; CC -!- COFACTOR: CC Name=heme; Xref=ChEBI:CHEBI:30413; CC Evidence={ECO:0000269|PubMed:25062272}; CC -!- ACTIVITY REGULATION: Inhibited by plumbagin (By similarity). Activated CC by phorbol 12-myristate 13-acetate (PMA). Activated by insulin. CC Inhibited by diphenylene iodonium. {ECO:0000250|UniProtKB:Q9JHI8, CC ECO:0000269|PubMed:14966267, ECO:0000269|PubMed:15572675, CC ECO:0000269|PubMed:16019190, ECO:0000269|PubMed:16324151}. CC -!- SUBUNIT: Interacts with protein disulfide isomerase (By similarity). CC Interacts with, relocalizes and stabilizes CYBA/p22phox. Interacts with CC TLR4. Interacts with PPP1R15A (PubMed:26742780). CC {ECO:0000250|UniProtKB:Q924V1, ECO:0000269|PubMed:15356101, CC ECO:0000269|PubMed:15927447}. CC -!- INTERACTION: CC Q9NPH5; O00206: TLR4; NbExp=4; IntAct=EBI-11301574, EBI-528701; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:15572675, ECO:0000269|PubMed:15927447, CC ECO:0000269|PubMed:21343298, ECO:0000269|PubMed:26742780}; Multi-pass CC membrane protein {ECO:0000255}. Cell membrane CC {ECO:0000269|PubMed:16019190, ECO:0000269|PubMed:21343298}; Multi-pass CC membrane protein {ECO:0000255}. Cell junction, focal adhesion CC {ECO:0000250|UniProtKB:Q924V1}. Nucleus {ECO:0000269|PubMed:16324151}. CC -!- SUBCELLULAR LOCATION: [Isoform 4]: Nucleus CC {ECO:0000269|PubMed:23393389}. Nucleus, nucleolus CC {ECO:0000269|PubMed:23393389}. Cytoplasm {ECO:0000269|PubMed:15721269}. CC Cytoplasm, perinuclear region {ECO:0000269|PubMed:15721269}. CC -!- SUBCELLULAR LOCATION: [Isoform 3]: Cytoplasm CC {ECO:0000269|PubMed:15721269}. Cytoplasm, perinuclear region CC {ECO:0000269|PubMed:15721269}. CC -!- SUBCELLULAR LOCATION: [Isoform 5]: Cytoplasm CC {ECO:0000269|PubMed:15721269}. Cytoplasm, perinuclear region CC {ECO:0000269|PubMed:15721269}. CC -!- SUBCELLULAR LOCATION: [Isoform 6]: Cytoplasm CC {ECO:0000269|PubMed:15721269}. Cytoplasm, perinuclear region CC {ECO:0000269|PubMed:15721269}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=9; CC Name=1; CC IsoId=Q9NPH5-1; Sequence=Displayed; CC Name=2; Synonyms=Nox4A; CC IsoId=Q9NPH5-2; Sequence=VSP_019052; CC Name=3; Synonyms=Nox4E; CC IsoId=Q9NPH5-3; Sequence=VSP_019053, VSP_019058; CC Name=4; Synonyms=28 kDa, Nox4D; CC IsoId=Q9NPH5-4; Sequence=VSP_019053; CC Name=5; Synonyms=Nox4C; CC IsoId=Q9NPH5-5; Sequence=VSP_019056, VSP_019057; CC Name=6; Synonyms=Nox4B; CC IsoId=Q9NPH5-6; Sequence=VSP_019058; CC Name=7; CC IsoId=Q9NPH5-7; Sequence=VSP_019054, VSP_019055; CC Name=8; CC IsoId=Q9NPH5-8; Sequence=VSP_053826; CC Name=9; CC IsoId=Q9NPH5-9; Sequence=VSP_053826, VSP_019058; CC -!- TISSUE SPECIFICITY: Expressed by distal tubular cells in kidney cortex CC and in endothelial cells (at protein level). Widely expressed. Strongly CC expressed in kidney and to a lower extent in heart, adipocytes, CC hepatoma, endothelial cells, skeletal muscle, brain, several brain CC tumor cell lines and airway epithelial cells. CC {ECO:0000269|PubMed:11032835, ECO:0000269|PubMed:11376945, CC ECO:0000269|PubMed:15210697, ECO:0000269|PubMed:16324151}. CC -!- DEVELOPMENTAL STAGE: Expressed in fetal kidney and fetal liver. CC {ECO:0000269|PubMed:10869423, ECO:0000269|PubMed:11032835, CC ECO:0000269|PubMed:11376945}. CC -!- INDUCTION: By 7-ketocholesterol (at protein level). CC {ECO:0000269|PubMed:15572675}. CC -!- PTM: [Isoform 4]: N-glycosylated and glycosylation is required for its CC proper function. {ECO:0000269|PubMed:15721269}. CC -!- PTM: [Isoform 3]: N-glycosylated. {ECO:0000269|PubMed:15721269}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF261943; AAF87572.1; -; mRNA. DR EMBL; AF254621; AAF68973.1; -; mRNA. DR EMBL; AB041035; BAA95695.1; -; mRNA. DR EMBL; AY288918; AAP41109.1; -; mRNA. DR EMBL; AJ704725; CAG28807.1; -; mRNA. DR EMBL; AJ704726; CAG28808.1; -; mRNA. DR EMBL; AJ704727; CAG28809.1; -; mRNA. DR EMBL; AJ704728; CAG28810.1; -; mRNA. DR EMBL; AJ704729; CAG28811.1; -; mRNA. DR EMBL; AK291830; BAF84519.1; -; mRNA. DR EMBL; AK298323; BAH12756.1; -; mRNA. DR EMBL; AP003400; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP001815; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AP002404; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC040105; AAH40105.1; -; mRNA. DR EMBL; BC051371; AAH51371.1; -; mRNA. DR CCDS; CCDS44695.1; -. [Q9NPH5-6] DR CCDS; CCDS44696.1; -. [Q9NPH5-8] DR CCDS; CCDS73361.1; -. [Q9NPH5-9] DR CCDS; CCDS8285.1; -. [Q9NPH5-1] DR RefSeq; NP_001137308.1; NM_001143836.2. [Q9NPH5-6] DR RefSeq; NP_001137309.1; NM_001143837.1. [Q9NPH5-8] DR RefSeq; NP_001278855.1; NM_001291926.1. [Q9NPH5-2] DR RefSeq; NP_001278856.1; NM_001291927.1. DR RefSeq; NP_001287924.1; NM_001300995.1. [Q9NPH5-9] DR RefSeq; NP_058627.1; NM_016931.4. [Q9NPH5-1] DR RefSeq; XP_011541159.1; XM_011542857.2. DR AlphaFoldDB; Q9NPH5; -. DR SMR; Q9NPH5; -. DR BioGRID; 119078; 23. DR IntAct; Q9NPH5; 3. DR STRING; 9606.ENSP00000263317; -. DR BindingDB; Q9NPH5; -. DR ChEMBL; CHEMBL1250375; -. DR DrugCentral; Q9NPH5; -. DR GuidetoPHARMACOLOGY; 3004; -. DR PeroxiBase; 5967; HsNOx04. DR TCDB; 5.B.1.1.2; the phagocyte (gp91(phox)) nadph oxidase family. DR GlyCosmos; Q9NPH5; 2 sites, No reported glycans. DR GlyGen; Q9NPH5; 2 sites. DR iPTMnet; Q9NPH5; -. DR PhosphoSitePlus; Q9NPH5; -. DR BioMuta; NOX4; -. DR DMDM; 212276447; -. DR MassIVE; Q9NPH5; -. DR PaxDb; 9606-ENSP00000263317; -. DR PeptideAtlas; Q9NPH5; -. DR ProteomicsDB; 16922; -. DR ProteomicsDB; 82003; -. [Q9NPH5-1] DR ProteomicsDB; 82004; -. [Q9NPH5-2] DR ProteomicsDB; 82005; -. [Q9NPH5-3] DR ProteomicsDB; 82006; -. [Q9NPH5-4] DR ProteomicsDB; 82008; -. [Q9NPH5-6] DR Antibodypedia; 17747; 761 antibodies from 38 providers. DR DNASU; 50507; -. DR Ensembl; ENST00000263317.9; ENSP00000263317.4; ENSG00000086991.13. [Q9NPH5-1] DR Ensembl; ENST00000343727.9; ENSP00000344747.5; ENSG00000086991.13. [Q9NPH5-8] DR Ensembl; ENST00000375979.7; ENSP00000365146.3; ENSG00000086991.13. [Q9NPH5-4] DR Ensembl; ENST00000393282.2; ENSP00000376961.2; ENSG00000086991.13. [Q9NPH5-7] DR Ensembl; ENST00000424319.5; ENSP00000412446.1; ENSG00000086991.13. [Q9NPH5-8] DR Ensembl; ENST00000527956.5; ENSP00000433797.1; ENSG00000086991.13. [Q9NPH5-8] DR Ensembl; ENST00000529343.5; ENSP00000435474.1; ENSG00000086991.13. [Q9NPH5-5] DR Ensembl; ENST00000531342.5; ENSP00000435039.1; ENSG00000086991.13. [Q9NPH5-3] DR Ensembl; ENST00000532825.5; ENSP00000434924.1; ENSG00000086991.13. [Q9NPH5-9] DR Ensembl; ENST00000534731.5; ENSP00000436892.1; ENSG00000086991.13. [Q9NPH5-6] DR GeneID; 50507; -. DR KEGG; hsa:50507; -. DR MANE-Select; ENST00000263317.9; ENSP00000263317.4; NM_016931.5; NP_058627.2. DR UCSC; uc001pct.4; human. [Q9NPH5-1] DR AGR; HGNC:7891; -. DR CTD; 50507; -. DR DisGeNET; 50507; -. DR GeneCards; NOX4; -. DR HGNC; HGNC:7891; NOX4. DR HPA; ENSG00000086991; Tissue enriched (kidney). DR MIM; 605261; gene. DR neXtProt; NX_Q9NPH5; -. DR OpenTargets; ENSG00000086991; -. DR PharmGKB; PA31692; -. DR VEuPathDB; HostDB:ENSG00000086991; -. DR eggNOG; KOG0039; Eukaryota. DR GeneTree; ENSGT00940000159621; -. DR HOGENOM; CLU_005646_3_1_1; -. DR InParanoid; Q9NPH5; -. DR OMA; AFWYTHQ; -. DR OrthoDB; 367877at2759; -. DR PhylomeDB; Q9NPH5; -. DR TreeFam; TF105354; -. DR PathwayCommons; Q9NPH5; -. DR Reactome; R-HSA-3299685; Detoxification of Reactive Oxygen Species. DR Reactome; R-HSA-9702518; STAT5 activation downstream of FLT3 ITD mutants. DR Reactome; R-HSA-9703465; Signaling by FLT3 fusion proteins. DR SignaLink; Q9NPH5; -. DR SIGNOR; Q9NPH5; -. DR BioGRID-ORCS; 50507; 12 hits in 1156 CRISPR screens. DR ChiTaRS; NOX4; human. DR GeneWiki; NOX4; -. DR GenomeRNAi; 50507; -. DR Pharos; Q9NPH5; Tchem. DR PRO; PR:Q9NPH5; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; Q9NPH5; Protein. DR Bgee; ENSG00000086991; Expressed in calcaneal tendon and 119 other cell types or tissues. DR ExpressionAtlas; Q9NPH5; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. DR GO; GO:0005925; C:focal adhesion; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; TAS:UniProtKB. DR GO; GO:0005739; C:mitochondrion; ISS:ARUK-UCL. DR GO; GO:0043020; C:NADPH oxidase complex; IBA:GO_Central. DR GO; GO:0005730; C:nucleolus; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0097038; C:perinuclear endoplasmic reticulum; ISS:ARUK-UCL. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0009055; F:electron transfer activity; TAS:UniProtKB. DR GO; GO:0050660; F:flavin adenine dinucleotide binding; TAS:UniProtKB. DR GO; GO:0020037; F:heme binding; IDA:UniProtKB. DR GO; GO:0072341; F:modified amino acid binding; IDA:UniProtKB. DR GO; GO:0016174; F:NAD(P)H oxidase H2O2-forming activity; IDA:UniProtKB. DR GO; GO:0106294; F:NADPH oxidase H202-forming activity; IEA:RHEA. DR GO; GO:0000166; F:nucleotide binding; TAS:UniProtKB. DR GO; GO:0019826; F:oxygen sensor activity; TAS:UniProtKB. DR GO; GO:1990782; F:protein tyrosine kinase binding; ISS:ARUK-UCL. DR GO; GO:0016175; F:superoxide-generating NAD(P)H oxidase activity; IDA:UniProtKB. DR GO; GO:0106292; F:superoxide-generating NADPH oxidase activity; IEA:RHEA. DR GO; GO:0045453; P:bone resorption; IEA:Ensembl. DR GO; GO:0055007; P:cardiac muscle cell differentiation; IEA:Ensembl. DR GO; GO:0000902; P:cell morphogenesis; ISS:UniProtKB. DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl. DR GO; GO:0006952; P:defense response; IBA:GO_Central. DR GO; GO:0010467; P:gene expression; IMP:CACAO. DR GO; GO:0003015; P:heart process; IGI:ARUK-UCL. DR GO; GO:0050667; P:homocysteine metabolic process; IDA:UniProtKB. DR GO; GO:0006954; P:inflammatory response; TAS:UniProtKB. DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB. DR GO; GO:2000573; P:positive regulation of DNA biosynthetic process; IEA:Ensembl. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IEA:Ensembl. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IEA:Ensembl. DR GO; GO:0061098; P:positive regulation of protein tyrosine kinase activity; ISS:ARUK-UCL. DR GO; GO:1903409; P:reactive oxygen species biosynthetic process; NAS:ARUK-UCL. DR GO; GO:0042554; P:superoxide anion generation; ISS:UniProtKB. DR GO; GO:0006801; P:superoxide metabolic process; IDA:CACAO. DR CDD; cd06186; NOX_Duox_like_FAD_NADP; 1. DR Gene3D; 3.40.50.80; Nucleotide-binding domain of ferredoxin-NADP reductase (FNR) module; 1. DR Gene3D; 2.40.30.10; Translation factors; 1. DR InterPro; IPR000778; Cyt_b245_heavy_chain. DR InterPro; IPR013112; FAD-bd_8. DR InterPro; IPR017927; FAD-bd_FR_type. DR InterPro; IPR013130; Fe3_Rdtase_TM_dom. DR InterPro; IPR013121; Fe_red_NAD-bd_6. DR InterPro; IPR039261; FNR_nucleotide-bd. DR InterPro; IPR017938; Riboflavin_synthase-like_b-brl. DR PANTHER; PTHR11972; NADPH OXIDASE; 1. DR PANTHER; PTHR11972:SF209; NADPH OXIDASE 4; 1. DR Pfam; PF08022; FAD_binding_8; 1. DR Pfam; PF01794; Ferric_reduct; 1. DR Pfam; PF08030; NAD_binding_6; 1. DR PRINTS; PR00466; GP91PHOX. DR SUPFAM; SSF52343; Ferredoxin reductase-like, C-terminal NADP-linked domain; 1. DR SUPFAM; SSF63380; Riboflavin synthase domain-like; 1. DR PROSITE; PS51384; FAD_FR; 1. DR Genevisible; Q9NPH5; HS. PE 1: Evidence at protein level; KW Alternative splicing; Cell junction; Cell membrane; Cytoplasm; KW Disulfide bond; Endoplasmic reticulum; Glycoprotein; Membrane; NADP; KW Nucleus; Oxidoreductase; Reference proteome; Transmembrane; KW Transmembrane helix. FT CHAIN 1..578 FT /note="NADPH oxidase 4" FT /id="PRO_0000238980" FT TOPO_DOM 1..16 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 17..37 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 38..62 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 63..83 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 84..103 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 104..124 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 125..154 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 155..175 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 176..188 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 189..209 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 210..424 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 425..445 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 446..578 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 58..303 FT /note="Ferric oxidoreductase" FT DOMAIN 304..419 FT /note="FAD-binding FR-type" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00716" FT REGION 218..273 FT /note="E-loop; essential for H2O2 generating catalytic FT activity" FT /evidence="ECO:0000269|PubMed:21343298" FT REGION 248..575 FT /note="Mediates interaction with TLR4" FT /evidence="ECO:0000269|PubMed:15356101" FT CARBOHYD 133 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 230 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 1..74 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15721269" FT /id="VSP_019052" FT VAR_SEQ 1..24 FT /note="Missing (in isoform 8 and isoform 9)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_053826" FT VAR_SEQ 52..358 FT /note="Missing (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|PubMed:15721269" FT /id="VSP_019053" FT VAR_SEQ 52..54 FT /note="LGL -> ELS (in isoform 7)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_019054" FT VAR_SEQ 55..578 FT /note="Missing (in isoform 7)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_019055" FT VAR_SEQ 211..224 FT /note="GLLKYQTNLDTHPP -> VQLKPKQHLGFILK (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15721269" FT /id="VSP_019056" FT VAR_SEQ 225..578 FT /note="Missing (in isoform 5)" FT /evidence="ECO:0000303|PubMed:15721269" FT /id="VSP_019057" FT VAR_SEQ 407..446 FT /note="Missing (in isoform 3, isoform 6 and isoform 9)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15210697, ECO:0000303|PubMed:15721269" FT /id="VSP_019058" FT VARIANT 315 FT /note="M -> I (in dbSNP:rs317139)" FT /evidence="ECO:0000269|PubMed:10869423, FT ECO:0000269|PubMed:11032835, ECO:0000269|PubMed:11376945, FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15210697, FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:15721269" FT /id="VAR_047114" FT MUTAGEN 16 FT /note="H->Q: 50% reduction in H2O2 generation, without any FT effect on superoxide generation." FT /evidence="ECO:0000269|PubMed:21343298" FT MUTAGEN 47 FT /note="H->Q: No effect on H2O2 or superoxide generation." FT /evidence="ECO:0000269|PubMed:21343298" FT MUTAGEN 218..235 FT /note="Missing: Loss of H2O2 generation with predominant FT generation of superoxide. No effect on localization to the FT endoplasmic reticulum." FT /evidence="ECO:0000269|PubMed:21343298" FT MUTAGEN 222 FT /note="H->Q: Loss of H2O2 generation with predominant FT generation of superoxide." FT /evidence="ECO:0000269|PubMed:21343298, FT ECO:0000269|PubMed:25062272" FT MUTAGEN 226 FT /note="C->V: Loss of H2O2 generation with predominant FT generation of superoxide." FT /evidence="ECO:0000269|PubMed:21343298" FT MUTAGEN 246 FT /note="H->Q: No effect on H2O2 or superoxide generation." FT /evidence="ECO:0000269|PubMed:21343298" FT MUTAGEN 248 FT /note="H->Q: No effect on H2O2 or superoxide generation." FT /evidence="ECO:0000269|PubMed:21343298" FT MUTAGEN 264..273 FT /note="Missing: Loss of H2O2 generation with predominant FT generation of superoxide. No effect on localization to the FT endoplasmic reticulum." FT /evidence="ECO:0000269|PubMed:21343298" FT MUTAGEN 270 FT /note="C->V: Loss of H2O2 generation with predominant FT generation of superoxide." FT /evidence="ECO:0000269|PubMed:21343298" FT MUTAGEN 304 FT /note="R->RGT: Partial loss of catalytic activity. No FT effect on CYBA localization." FT /evidence="ECO:0000269|PubMed:15927447" FT MUTAGEN 575..578 FT /note="Missing: Partial loss of catalytic activity. No FT effect on CYBA localization." FT /evidence="ECO:0000269|PubMed:15927447" FT CONFLICT 286 FT /note="W -> C (in Ref. 6; BAH12756)" FT /evidence="ECO:0000305" SQ SEQUENCE 578 AA; 66932 MW; D150A92CC71DD40D CRC64; MAVSWRSWLA NEGVKHLCLF IWLSMNVLLF WKTFLLYNQG PEYHYLHQML GLGLCLSRAS ASVLNLNCSL ILLPMCRTLL AYLRGSQKVP SRRTRRLLDK SRTFHITCGV TICIFSGVHV AAHLVNALNF SVNYSEDFVE LNAARYRDED PRKLLFTTVP GLTGVCMVVV LFLMITASTY AIRVSNYDIF WYTHNLFFVF YMLLTLHVSG GLLKYQTNLD THPPGCISLN RTSSQNISLP EYFSEHFHEP FPEGFSKPAE FTQHKFVKIC MEEPRFQANF PQTWLWISGP LCLYCAERLY RYIRSNKPVT IISVMSHPSD VMEIRMVKEN FKARPGQYIT LHCPSVSALE NHPFTLTMCP TETKATFGVH LKIVGDWTER FRDLLLPPSS QDSEILPFIQ SRNYPKLYID GPFGSPFEES LNYEVSLCVA GGIGVTPFAS ILNTLLDDWK PYKLRRLYFI WVCRDIQSFR WFADLLCMLH NKFWQENRPD YVNIQLYLSQ TDGIQKIIGE KYHALNSRLF IGRPRWKLLF DEIAKYNRGK TVGVFCCGPN SLSKTLHKLS NQNNSYGTRF EYNKESFS //