NOX2 explained

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).^[1] The protein is a superoxide generating enzyme which forms reactive oxygen species (ROS).

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.^[2] 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.^[3] 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.^[4]

Evidence has shown that it plays an important role in atherosclerotic lesion development in the aortic arch, thoracic, and abdominal aorta. ^{[5] [6]}

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.^[7] Furthermore, it increases global post-reperfusion oxidative stress, likely due to decreased STAT3 and Erk phosphorylation.^[7]

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).^[8] Endothelial Nox2 limits NF-κB activation and TLR4 expression, which in turn attenuates the severity of hypotension and systemic inflammation induced by lipopolysaccharides (LPS).^[9]

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.^[10]

Clinical significance

CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD).^[11] 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.^[1] At least 34 disease-causing mutations in this gene have been discovered.^[12]

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.^[6]

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.^[13]

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.^[14]

CYBB transcript levels are upregulated in the lung parenchyma of smokers. ^[15]

Interactions

Nox2 has been shown to interact directly with podocyte TRPC6 channels.^[16]

Further reading

• Bolscher BG, de Boer M, de Klein A, Weening RS, Roos D . Point mutations in the beta-subunit of cytochrome b558 leading to X-linked chronic granulomatous disease . Blood . 77 . 11 . 2482–2487 . June 1991 . 1710153 . 10.1182/blood.V77.11.2482.2482 . free .
• Nong Y, Kandil O, Tobin EH, Rose RM, Remold HG . 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 . January 1991 . 1905983 . 10.1016/0008-8749(91)90002-S .
• Dinauer MC, Pierce EA, Bruns GA, Curnutte JT, Orkin SH . 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 . November 1990 . 2243141 . 296926 . 10.1172/JCI114898 .
• Royer-Pokora B, Kunkel LM, Monaco AP, Goff SC, Newburger PE, Baehner RL, Cole FS, Curnutte JT, Orkin SH . 6 . Cloning the gene for an inherited human disorder--chronic granulomatous disease--on the basis of its chromosomal location . Nature . 322 . 6074 . 32–38 . 1986 . 2425263 . 10.1038/322032a0 . free . 4332080 . 1986Natur.322...32R . 2027.42/62926 .
• Dinauer MC, Curnutte JT, Rosen H, Orkin SH . 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 . December 1989 . 2556453 . 304086 . 10.1172/JCI114393 .
• Dinauer MC, Orkin SH, Brown R, Jesaitis AJ, Parkos CA . 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 . 1987 . 3600768 . 10.1038/327717a0 . 4360786 . 1987Natur.327..717D .
• Teahan C, Rowe P, Parker P, Totty N, Segal AW . The X-linked chronic granulomatous disease gene codes for the beta-chain of cytochrome b-245 . Nature . 327 . 6124 . 720–721 . 1987 . 3600769 . 10.1038/327720a0 . 4357532 . 1987Natur.327..720T .
• Rabbani H, de Boer M, Ahlin A, Sundin U, Elinder G, Hammarström L, Palmblad J, Smith CI, Roos D . 6 . 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 . October 1993 . 7694872 . 10.1111/j.1600-0609.1993.tb00634.x . 6702733 .
• Pollock JD, Williams DA, Gifford MA, Li LL, Du X, Fisherman J, Orkin SH, Doerschuk CM, Dinauer MC . 6 . Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production . Nature Genetics . 9 . 2 . 202–209 . February 1995 . 7719350 . 10.1038/ng0295-202 . 13341129 .
• Ariga T, Sakiyama Y, Matsumoto S . 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 . October 1994 . 7927345 . 10.1007/BF00201609 . 33195989 .
• Leto TL, Adams AG, de Mendez I . 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 . October 1994 . 7938008 . 45079 . 10.1073/pnas.91.22.10650 . free . 1994PNAS...9110650L .
• Ariga T, Sakiyama Y, Tomizawa K, Imajoh-Ohmi S, Kanegasaki S, Matsumoto S . 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 . June 1993 . 8101486 . 10.1007/BF01955051 . 8525067 .
• Leusen JH, de Boer M, Bolscher BG, Hilarius PM, Weening RS, Ochs HD, Roos D, Verhoeven AJ . 6 . 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 . May 1994 . 8182143 . 294341 . 10.1172/JCI117207 .
• Meindl A, Carvalho MR, Herrmann K, Lorenz B, Achatz H, Lorenz B, Apfelstedt-Sylla E, Wittwer B, Ross M, Meitinger T . 6 . 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 . December 1995 . 8634708 . 10.1093/hmg/4.12.2339 .
• Sathyamoorthy M, de Mendez I, Adams AG, Leto TL . p40(phox) down-regulates NADPH oxidase activity through interactions with its SH3 domain . The Journal of Biological Chemistry . 272 . 14 . 9141–9146 . April 1997 . 9083043 . 10.1074/jbc.272.14.9141 . free .
• Eklund EA, Kakar R . 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 . April 1997 . 9083071 . 10.1074/jbc.272.14.9344 . free .
• Jendrossek V, Ritzel A, Neubauer B, Heyden S, Gahr M . 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 . February 1997 . 9111587 . 10.1111/j.1600-0609.1997.tb00928.x . 11920601 .
• Rae J, Newburger PE, Dinauer MC, Noack D, Hopkins PJ, Kuruto R, Curnutte JT . 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 . June 1998 . 9585602 . 1377153 . 10.1086/301874 .
• Ariga T, Furuta H, Cho K, Sakiyama Y . 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 . July 1998 . 9667376 . 10.1203/00006450-199807000-00014 . free .
• Kumatori A, Faizunnessa NN, Suzuki S, Moriuchi T, Kurozumi H, Nakamura M . 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 . October 1998 . 9790760 . 10.1006/geno.1998.5510 .

Notes and References

1. Web site: Entrez Gene: CYBB cytochrome b-245, beta polypeptide (chronic granulomatous disease).
2. Hervé C, Tonon T, Collén J, Corre E, Boyen C . NADPH oxidases in Eukaryotes: red algae provide new hints! . Current Genetics . 49 . 3 . 190–204 . March 2006 . 16344959 . 10.1007/s00294-005-0044-z . 19791715 .
3. Kawahara T, Lambeth JD . Molecular evolution of Phox-related regulatory subunits for NADPH oxidase enzymes . BMC Evolutionary Biology . 7 . 178 . September 2007 . 1 . 17900370 . 2121648 . 10.1186/1471-2148-7-178 . 2007BMCEE...7..178K . free .
4. Aguirre J, Lambeth JD . Nox enzymes from fungus to fly to fish and what they tell us about Nox function in mammals . Free Radical Biology & Medicine . 49 . 9 . 1342–1353 . November 2010 . 20696238 . 2981133 . 10.1016/j.freeradbiomed.2010.07.027 .
5. Sorescu D, Weiss D, Lassègue B, Clempus RE, Szöcs K, Sorescu GP, Valppu L, Quinn MT, Lambeth JD, Vega JD, Taylor WR, Griendling KK . 6 . Superoxide production and expression of nox family proteins in human atherosclerosis . Circulation . 105 . 12 . 1429–1435 . March 2002 . 11914250 . 10.1161/01.cir.0000012917.74432.66 . free .
6. Chaubey S, Jones GE, Shah AM, Cave AC, Wells CM . Nox2 is required for macrophage chemotaxis towards CSF-1 . PLOS ONE . 8 . 2 . e54869 . 2013 . 23383302 . 3562318 . 10.1371/journal.pone.0054869 . free . 2013PLoSO...854869C .
7. Braunersreuther V, Montecucco F, Asrih M, Ashri M, Pelli G, Galan K, Frias M, Burger F, Quinderé AL, Montessuit C, Krause KH, Mach F, Jaquet V . 6 . Role of NADPH oxidase isoforms NOX1, NOX2 and NOX4 in myocardial ischemia/reperfusion injury . Journal of Molecular and Cellular Cardiology . 64 . 99–107 . November 2013 . 24051369 . 10.1016/j.yjmcc.2013.09.007 . 20225141 .
8. Hernandes MS, D'Avila JC, Trevelin SC, Reis PA, Kinjo ER, Lopes LR, Castro-Faria-Neto HC, Cunha FQ, Britto LR, Bozza FA . 6 . The role of Nox2-derived ROS in the development of cognitive impairment after sepsis . Journal of Neuroinflammation . 11 . 1 . 36 . February 2014 . 24571599 . 3974031 . 10.1186/1742-2094-11-36 . free .
9. Trevelin SC, Sag CM, Zhang M, Alves-Filho JC, Cunha TM, Santos CX, Sawyer G, Murray T, Brewer A, Laurindo FR, Protti A, Lopes LR, Ivetic A, Cunha FQ, Shah AM . 6 . Endothelial Nox2 Limits Systemic Inflammation and Hypotension in Endotoxemia by Controlling Expression of Toll-Like Receptor 4 . Shock . 56 . 2 . 268–277 . August 2021 . 34276040 . 8284354 . 10.1097/SHK.0000000000001706 .
10. Chan SL, Baumbach GL . Deficiency of Nox2 prevents angiotensin II-induced inward remodeling in cerebral arterioles . Frontiers in Physiology . 4 . 133 . 26 June 2013 . 23805104 . 3693079 . 10.3389/fphys.2013.00133 . free .
11. Web site: CYBB cytochrome b-245 beta chain [Homo sapiens (human)] - Gene - NCBI ]. 2022-05-10 . www.ncbi.nlm.nih.gov.
12. Šimčíková D, Heneberg P . Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases . Scientific Reports . 9 . 1 . 18577 . December 2019 . 31819097 . 6901466 . 10.1038/s41598-019-54976-4 . 2019NatSR...918577S .
13. Loffredo L, Carnevale R, Cangemi R, Angelico F, Augelletti T, Di Santo S, Calabrese CM, Della Volpe L, Pignatelli P, Perri L, Basili S, Violi F . 6 . NOX2 up-regulation is associated with artery dysfunction in patients with peripheral artery disease . International Journal of Cardiology . 165 . 1 . 184–192 . April 2013 . 22336250 . 10.1016/j.ijcard.2012.01.069 .
14. Rojas M, Zhang W, Xu Z, Lemtalsi T, Chandler P, Toque HA, Caldwell RW, Caldwell RB . 6 . Requirement of NOX2 expression in both retina and bone marrow for diabetes-induced retinal vascular injury . PLOS ONE . 8 . 12 . e84357 . 2013 . 24358357 . 3866146 . 10.1371/journal.pone.0084357 . free . 2013PLoSO...884357R .
15. Pintarelli G, Noci S, Maspero D, Pettinicchio A, Dugo M, De Cecco L, Incarbone M, Tosi D, Santambrogio L, Dragani TA, Colombo F . 6 . Cigarette smoke alters the transcriptome of non-involved lung tissue in lung adenocarcinoma patients . Scientific Reports . 9 . 1 . 13039 . September 2019 . 31506599 . 6736939 . 10.1038/s41598-019-49648-2 . 2019NatSR...913039P .
16. Kim EY, Anderson M, Wilson C, Hagmann H, Benzing T, Dryer SE . NOX2 interacts with podocyte TRPC6 channels and contributes to their activation by diacylglycerol: essential role of podocin in formation of this complex . American Journal of Physiology. Cell Physiology . 305 . 9 . C960–C971 . November 2013 . 23948707 . 10.1152/ajpcell.00191.2013 .