NOX2

This article is about a human gene. For the airport in Canada, see Kugaaruk Airport.

NADPH oxidase 2 (Nox2), also known as cytochrome b(558) subunit beta or Cytochrome b-245 heavy chain, is a protein that in humans is encoded by the NOX2 gene (also called CYBB gene). The protein is a superoxide generating enzyme which forms reactive oxygen species (ROS).

CYBB
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3A1F
Identifiers
Aliases	CYBB, AMCBX2, CGD, GP91-1, GP91-PHOX, GP91PHOX, IMD34, NOX2, p91-PHOX, cytochrome b-245 beta chain, CGDX
External IDs	OMIM: 300481; MGI: 88574; HomoloGene: 68054; GeneCards: CYBB; OMA:CYBB - orthologs
Gene location (Human) Chr. X chromosome (human) Band Xp21.1-p11.4 Start 37,780,018 bp End 37,813,461 bp
Gene location (Mouse) Chr. X chromosome (mouse) Band X|X A1.1 Start 9,301,491 bp End 9,354,010 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte granulocyte bone marrow bone marrow cells synovial joint blood trabecular bone appendix lymph node decidua Top expressed in granulocyte stroma of bone marrow mesenteric lymph nodes right lung lobe spleen lumbar spinal ganglion tibiofemoral joint calvaria blood ankle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function flavin adenine dinucleotide binding superoxide-generating NAD(P)H oxidase activity metal ion binding voltage-gated ion channel activity protein binding heme binding protein heterodimerization activity electron transfer activity oxidoreductase activity Cellular component cytoplasm integral component of membrane phagocytic vesicle membrane membrane plasma membrane integral component of plasma membrane NADPH oxidase complex perinuclear region of cytoplasm phagocytic vesicle Golgi apparatus endoplasmic reticulum soma intracellular anatomical structure endoplasmic reticulum membrane rough endoplasmic reticulum dendrite nuclear envelope specific granule membrane tertiary granule membrane perinuclear endoplasmic reticulum Biological process regulation of ion transmembrane transport ion transport superoxide anion generation respiratory burst vascular endothelial growth factor receptor signaling pathway hydrogen peroxide biosynthetic process innate immune response inflammatory response superoxide metabolic process cellular response to L-glutamine positive regulation of angiogenesis response to angiotensin response to nutrient cellular response to hypoxia hypoxia-inducible factor-1alpha signaling pathway cellular response to cadmium ion cellular response to ethanol response to aldosterone neutrophil degranulation cellular response to oxidative stress electron transport chain ion transmembrane transport antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent defense response cell redox homeostasis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1536 13058 Ensembl ENSG00000165168 ENSMUSG00000015340 UniProt P04839 Q61093 RefSeq (mRNA) NM_000397 NM_007807 RefSeq (protein) NP_000388 NP_031833 Location (UCSC) Chr X: 37.78 – 37.81 Mb Chr X: 9.3 – 9.35 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Function

The CYBB gene encode cytochrome b-245, beta chain. This protein is subunit of a group of proteins that forms an enzyme complex called NADPH oxidase, which plays an essential role in the immune system. Within this complex, the cytochrome b-245, beta chain has an alpha chain partner (produced from the CYBA gene). Both alpha and beta chains are required for either to function and the NADPH oxidase complex requires both chains in order to be functional. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes.

Nox2 is the catalytic, membrane-bound subunit of NADPH oxidase. It is inactive until it binds to the membrane-anchored p22phox, forming the heterodimer known as flavocytochrome b558. After activation, the regulatory subunits p67phox, p47phox, p40phox and a GTPase, typically Rac, are recruited to the complex to form NADPH oxidase on the plasma membrane or phagosomal membrane. Nox2 itself is composed of an N-terminal transmembrane domain that binds two heme groups, and a C-terminal domain that is able to bind to FAD and NADPH.

Evidence has shown that it plays an important role in atherosclerotic lesion development in the aortic arch, thoracic, and abdominal aorta.

It has also been shown to play a part in determining the size of a myocardial infarction due to its connection to ROS, which play a role in myocardial reperfusion injury. This was a result of the relation between Nox2 and signaling necessary for neutrophil recruitment. Furthermore, it increases global post-reperfusion oxidative stress, likely due to decreased STAT3 and Erk phosphorylation.

In addition, it appears that hippocampal oxidative stress is increased in septic animals due to the actions of Nox2. This connection also came about through the actions of the chemically active ROS, which work as one of the main components that help in the development of neuroinflammation associated with sepsis-associated encephalopathy (SAE). Endothelial Nox2 limits NF-κB activation and TLR4 expression, which in turn attenuates the severity of hypotension and systemic inflammation induced by lipopolysaccharides (LPS).

It seems that Nox2 also plays an important role in angiotensin II-mediated inward remodelling in cerebral arterioles due to the emittance of superoxides from Nox2-containing NADPH oxidases.

Clinical significance

CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). CGD is characterized by recurrent, severe infections to pathogens that are normally harmless to humans, such as the common mold Aspergillus niger, and can result from point mutations in the gene encoding Nox2. In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole. At least 34 disease-causing mutations in this gene have been discovered.

Since Nox2 was shown to play an essential role in determining the size of a myocardial infarction, the protein can be a potential target for drug medication due to its negative effect on myocardial reperfusion.

Recent evidence highly suggests that Nox2 generates ROS which contribute to reduce flow-mediated dilation (FMD) in patients with periphery artery disease (PAD). Scientists have gone to conclude that administering an antioxidant helps with inhibiting Nox2 activity and allowing in the improvement of arterial dilation.

Lastly, targeting Nox2 in the bone marrow could be a great therapeutic attempt at treating vascular injury during diabetic retinopathy (damage to the retina), because the Nox2-generated ROS which are produced by the bone-marrow derived cells & local retinal cells are accumulating the vascular injury in the diabetic retina area.

CYBB transcript levels are upregulated in the lung parenchyma of smokers.

Interactions

Nox2 has been shown to interact directly with podocyte TRPC6 channels.

Further reading

• Bolscher BG, de Boer M, de Klein A, Weening RS, Roos D (June 1991). "Point mutations in the beta-subunit of cytochrome b558 leading to X-linked chronic granulomatous disease". Blood. 77 (11): 2482–2487. doi:10.1182/blood.V77.11.2482.2482. PMID 1710153.
• Nong Y, Kandil O, Tobin EH, Rose RM, Remold HG (January 1991). "The HIV core protein p24 inhibits interferon-gamma-induced increase of HLA-DR and cytochrome b heavy chain mRNA levels in the human monocyte-like cell line THP1". Cellular Immunology. 132 (1): 10–16. doi:10.1016/0008-8749(91)90002-S. PMID 1905983.
• Dinauer MC, Pierce EA, Bruns GA, Curnutte JT, Orkin SH (November 1990). "Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome-negative autosomal recessive chronic granulomatous disease". The Journal of Clinical Investigation. 86 (5): 1729–1737. doi:10.1172/JCI114898. PMC 296926. PMID 2243141.
• Royer-Pokora B, Kunkel LM, Monaco AP, Goff SC, Newburger PE, Baehner RL, et al. (1986). "Cloning the gene for an inherited human disorder--chronic granulomatous disease--on the basis of its chromosomal location". Nature. 322 (6074): 32–38. Bibcode:1986Natur.322...32R. doi:10.1038/322032a0. hdl:2027.42/62926. PMID 2425263. S2CID 4332080.
• Dinauer MC, Curnutte JT, Rosen H, Orkin SH (December 1989). "A missense mutation in the neutrophil cytochrome b heavy chain in cytochrome-positive X-linked chronic granulomatous disease". The Journal of Clinical Investigation. 84 (6): 2012–2016. doi:10.1172/JCI114393. PMC 304086. PMID 2556453.
• Dinauer MC, Orkin SH, Brown R, Jesaitis AJ, Parkos CA (1987). "The glycoprotein encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex". Nature. 327 (6124): 717–720. Bibcode:1987Natur.327..717D. doi:10.1038/327717a0. PMID 3600768. S2CID 4360786.
• Teahan C, Rowe P, Parker P, Totty N, Segal AW (1987). "The X-linked chronic granulomatous disease gene codes for the beta-chain of cytochrome b-245". Nature. 327 (6124): 720–721. Bibcode:1987Natur.327..720T. doi:10.1038/327720a0. PMID 3600769. S2CID 4357532.
• Rabbani H, de Boer M, Ahlin A, Sundin U, Elinder G, Hammarström L, et al. (October 1993). "A 40-base-pair duplication in the gp91-phox gene leading to X-linked chronic granulomatous disease". European Journal of Haematology. 51 (4): 218–222. doi:10.1111/j.1600-0609.1993.tb00634.x. PMID 7694872. S2CID 6702733.
• Pollock JD, Williams DA, Gifford MA, Li LL, Du X, Fisherman J, et al. (February 1995). "Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production". Nature Genetics. 9 (2): 202–209. doi:10.1038/ng0295-202. PMID 7719350. S2CID 13341129.
• Ariga T, Sakiyama Y, Matsumoto S (October 1994). "Two novel point mutations in the cytochrome b 558 heavy chain gene, detected in two Japanese patients with X-linked chronic granulomatous disease". Human Genetics. 94 (4): 441. doi:10.1007/BF00201609. PMID 7927345. S2CID 33195989.
• Leto TL, Adams AG, de Mendez I (October 1994). "Assembly of the phagocyte NADPH oxidase: binding of Src homology 3 domains to proline-rich targets". Proceedings of the National Academy of Sciences of the United States of America. 91 (22): 10650–10654. Bibcode:1994PNAS...9110650L. doi:10.1073/pnas.91.22.10650. PMC 45079. PMID 7938008.
• Ariga T, Sakiyama Y, Tomizawa K, Imajoh-Ohmi S, Kanegasaki S, Matsumoto S (June 1993). "A newly recognized point mutation in the cytochrome b558 heavy chain gene replacing alanine57 by glutamic acid, in a patient with cytochrome b positive X-linked chronic granulomatous disease". European Journal of Pediatrics. 152 (6): 469–472. doi:10.1007/BF01955051. PMID 8101486. S2CID 8525067.
• Leusen JH, de Boer M, Bolscher BG, Hilarius PM, Weening RS, Ochs HD, et al. (May 1994). "A point mutation in gp91-phox of cytochrome b558 of the human NADPH oxidase leading to defective translocation of the cytosolic proteins p47-phox and p67-phox". The Journal of Clinical Investigation. 93 (5): 2120–2126. doi:10.1172/JCI117207. PMC 294341. PMID 8182143.
• Meindl A, Carvalho MR, Herrmann K, Lorenz B, Achatz H, Lorenz B, et al. (December 1995). "A gene (SRPX) encoding a sushi-repeat-containing protein is deleted in patients with X-linked retinitis pigmentosa". Human Molecular Genetics. 4 (12): 2339–2346. doi:10.1093/hmg/4.12.2339. PMID 8634708.
• Sathyamoorthy M, de Mendez I, Adams AG, Leto TL (April 1997). "p40(phox) down-regulates NADPH oxidase activity through interactions with its SH3 domain". The Journal of Biological Chemistry. 272 (14): 9141–9146. doi:10.1074/jbc.272.14.9141. PMID 9083043.
• Eklund EA, Kakar R (April 1997). "Identification and characterization of TF1(phox), a DNA-binding protein that increases expression of gp91(phox) in PLB985 myeloid leukemia cells". The Journal of Biological Chemistry. 272 (14): 9344–9355. doi:10.1074/jbc.272.14.9344. PMID 9083071.
• Jendrossek V, Ritzel A, Neubauer B, Heyden S, Gahr M (February 1997). "An in-frame triplet deletion within the gp91-phox gene in an adult X-linked chronic granulomatous disease patient with residual NADPH-oxidase activity". European Journal of Haematology. 58 (2): 78–85. doi:10.1111/j.1600-0609.1997.tb00928.x. PMID 9111587. S2CID 11920601.
• Rae J, Newburger PE, Dinauer MC, Noack D, Hopkins PJ, Kuruto R, Curnutte JT (June 1998). "X-Linked chronic granulomatous disease: mutations in the CYBB gene encoding the gp91-phox component of respiratory-burst oxidase". American Journal of Human Genetics. 62 (6): 1320–1331. doi:10.1086/301874. PMC 1377153. PMID 9585602.
• Ariga T, Furuta H, Cho K, Sakiyama Y (July 1998). "Genetic analysis of 13 families with X-linked chronic granulomatous disease reveals a low proportion of sporadic patients and a high proportion of sporadic carriers". Pediatric Research. 44 (1): 85–92. doi:10.1203/00006450-199807000-00014. PMID 9667376.
• Kumatori A, Faizunnessa NN, Suzuki S, Moriuchi T, Kurozumi H, Nakamura M (October 1998). "Nonhomologous recombination between the cytochrome b558 heavy chain gene (CYBB) and LINE-1 causes an X-linked chronic granulomatous disease". Genomics. 53 (2): 123–128. doi:10.1006/geno.1998.5510. PMID 9790760.

External links

• gp91phox+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human CYBB genome location and CYBB gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P04839 (Cytochrome b-245 heavy chain) at the PDBe-KB.