NOX2
NADPH oxidase 2(Nox2), also known ascytochrome b(558) subunit betaorCytochrome b-245 heavy chain,is aproteinthat in humans is encoded by theNOX2gene(also calledCYBBgene).[5]The protein is asuperoxidegenerating enzyme which formsreactive oxygen species(ROS).
Function
[edit]TheCYBBgene 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 theCYBAgene). 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 themicrobicidaloxidase system ofphagocytes.
Nox2 is the catalytic, membrane-bound subunit ofNADPH oxidase.It is inactive until it binds to the membrane-anchoredp22phox,forming the heterodimer known as flavocytochrome b558.[6]After activation, the regulatory subunitsp67phox,p47phox,p40phoxand aGTPase,typically Rac, are recruited to the complex to form NADPH oxidase on the plasma membrane or phagosomal membrane.[7]Nox2 itself is composed of an N-terminal transmembrane domain that binds twoheme groups,and a C-terminal domain that is able to bind toFADandNADPH.[8]
Evidence has shown that it plays an important role inatheroscleroticlesion development in theaortic arch,thoracic,andabdominal aorta.[9] [10]
It has also been shown to play a part in determining the size of amyocardial infarctiondue 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 forneutrophilrecruitment.[11] Furthermore, it increases global post-reperfusion oxidative stress, likely due to decreasedSTAT3andErkphosphorylation.[11]
In addition, it appears thathippocampaloxidative stress is increased insepticanimals 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 ofneuroinflammationassociated with sepsis-associatedencephalopathy(SAE).[12]Endothelial Nox2 limits NF-κB activation and TLR4 expression, which in turn attenuates the severity of hypotension and systemic inflammation induced by lipopolysaccharides (LPS).[13]
It seems that Nox2 also plays an important role inangiotensinII-mediated inward remodelling in cerebral arterioles due to the emittance of superoxides from Nox2-containingNADPH oxidases.[14]
Clinical significance
[edit]CYBB deficiency is one of five described biochemical defects associated withchronic granulomatous disease(CGD).[15]CGD is characterized by recurrent, severe infections to pathogens that are normally harmless to humans, such as the common moldAspergillus niger,and can result from point mutations in the gene encoding Nox2.[8]In this disorder, there is decreased activity of phagocyteNADPH oxidase;neutrophilsare able to phagocytize bacteria but cannot kill them in the phagocyticvacuoles.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.[5]At least 34 disease-causing mutations in this gene have been discovered.[16]
Since Nox2 was shown to play an essential role in determining the size of amyocardial infarction,the protein can be a potential target for drug medication due to its negative effect on myocardial reperfusion.[10]
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.[17]
Lastly, targeting Nox2 in the bone marrow could be a great therapeutic attempt at treating vascular injury duringdiabetic 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.[18]
CYBB transcript levels are upregulated in the lung parenchyma of smokers.[19]
Interactions
[edit]Nox2 has been shown to interact directly withpodocyteTRPC6 channels.[20]
References
[edit]- ^abcGRCh38: Ensembl release 89: ENSG00000165168–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000015340–Ensembl,May 2017
- ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ab"Entrez Gene: CYBB cytochrome b-245, beta polypeptide (chronic granulomatous disease)".
- ^Hervé C, Tonon T, Collén J, Corre E, Boyen C (March 2006). "NADPH oxidases in Eukaryotes: red algae provide new hints!".Current Genetics.49(3): 190–204.doi:10.1007/s00294-005-0044-z.PMID16344959.S2CID19791715.
- ^Kawahara T, Lambeth JD (September 2007)."Molecular evolution of Phox-related regulatory subunits for NADPH oxidase enzymes".BMC Evolutionary Biology.7(1): 178.Bibcode:2007BMCEE...7..178K.doi:10.1186/1471-2148-7-178.PMC2121648.PMID17900370.
- ^abAguirre J, Lambeth JD (November 2010)."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.doi:10.1016/j.freeradbiomed.2010.07.027.PMC2981133.PMID20696238.
- ^Sorescu D, Weiss D, Lassègue B, Clempus RE, Szöcs K, Sorescu GP, et al. (March 2002)."Superoxide production and expression of nox family proteins in human atherosclerosis".Circulation.105(12): 1429–1435.doi:10.1161/01.cir.0000012917.74432.66.PMID11914250.
- ^abChaubey S, Jones GE, Shah AM, Cave AC, Wells CM (2013)."Nox2 is required for macrophage chemotaxis towards CSF-1".PLOS ONE.8(2): e54869.Bibcode:2013PLoSO...854869C.doi:10.1371/journal.pone.0054869.PMC3562318.PMID23383302.
- ^abBraunersreuther V, Montecucco F, Asrih M, Ashri M, Pelli G, Galan K, et al. (November 2013)."Role of NADPH oxidase isoforms NOX1, NOX2 and NOX4 in myocardial ischemia/reperfusion injury".Journal of Molecular and Cellular Cardiology.64:99–107.doi:10.1016/j.yjmcc.2013.09.007.PMID24051369.S2CID20225141.
- ^Hernandes MS, D'Avila JC, Trevelin SC, Reis PA, Kinjo ER, Lopes LR, et al. (February 2014)."The role of Nox2-derived ROS in the development of cognitive impairment after sepsis".Journal of Neuroinflammation.11(1): 36.doi:10.1186/1742-2094-11-36.PMC3974031.PMID24571599.
- ^Trevelin SC, Sag CM, Zhang M, Alves-Filho JC, Cunha TM, Santos CX, et al. (August 2021)."Endothelial Nox2 Limits Systemic Inflammation and Hypotension in Endotoxemia by Controlling Expression of Toll-Like Receptor 4".Shock.56(2): 268–277.doi:10.1097/SHK.0000000000001706.PMC8284354.PMID34276040.
- ^Chan SL, Baumbach GL (26 June 2013)."Deficiency of Nox2 prevents angiotensin II-induced inward remodeling in cerebral arterioles".Frontiers in Physiology.4:133.doi:10.3389/fphys.2013.00133.PMC3693079.PMID23805104.
- ^"CYBB cytochrome b-245 beta chain [Homo sapiens (human)] - Gene - NCBI".www.ncbi.nlm.nih.gov.Retrieved2022-05-10.
- ^Šimčíková D, Heneberg P (December 2019)."Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases".Scientific Reports.9(1): 18577.Bibcode:2019NatSR...918577S.doi:10.1038/s41598-019-54976-4.PMC6901466.PMID31819097.
- ^Loffredo L, Carnevale R, Cangemi R, Angelico F, Augelletti T, Di Santo S, et al. (April 2013). "NOX2 up-regulation is associated with artery dysfunction in patients with peripheral artery disease".International Journal of Cardiology.165(1): 184–192.doi:10.1016/j.ijcard.2012.01.069.PMID22336250.
- ^Rojas M, Zhang W, Xu Z, Lemtalsi T, Chandler P, Toque HA, et al. (2013)."Requirement of NOX2 expression in both retina and bone marrow for diabetes-induced retinal vascular injury".PLOS ONE.8(12): e84357.Bibcode:2013PLoSO...884357R.doi:10.1371/journal.pone.0084357.PMC3866146.PMID24358357.
- ^Pintarelli G, Noci S, Maspero D, Pettinicchio A, Dugo M, De Cecco L, et al. (September 2019)."Cigarette smoke alters the transcriptome of non-involved lung tissue in lung adenocarcinoma patients".Scientific Reports.9(1): 13039.Bibcode:2019NatSR...913039P.doi:10.1038/s41598-019-49648-2.PMC6736939.PMID31506599.
- ^Kim EY, Anderson M, Wilson C, Hagmann H, Benzing T, Dryer SE (November 2013). "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.doi:10.1152/ajpcell.00191.2013.PMID23948707.
Further reading
[edit]- 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.PMID1710153.
- 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.PMID1905983.
- 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.PMC296926.PMID2243141.
- 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.PMID2425263.S2CID4332080.
- 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.PMC304086.PMID2556453.
- 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.PMID3600768.S2CID4360786.
- 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.PMID3600769.S2CID4357532.
- 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.PMID7694872.S2CID6702733.
- 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.PMID7719350.S2CID13341129.
- 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.PMID7927345.S2CID33195989.
- 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.PMC45079.PMID7938008.
- 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.PMID8101486.S2CID8525067.
- 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.PMC294341.PMID8182143.
- 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.PMID8634708.
- 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.PMID9083043.
- 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.PMID9083071.
- 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.PMID9111587.S2CID11920601.
- 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.PMC1377153.PMID9585602.
- 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.PMID9667376.
- 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.PMID9790760.
External links
[edit]- gp91phox+protein,+humanat the U.S. National Library of MedicineMedical Subject Headings(MeSH)
- HumanCYBBgenome location andCYBBgene details page in theUCSC Genome Browser.
- Overview of all the structural information available in thePDBforUniProt:P04839(Cytochrome b-245 heavy chain) at thePDBe-KB.