Biology:NOX2
 Generic protein structure example |
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. [4] 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]
References
- ↑ 1.0 1.1 "Entrez Gene: CYBB cytochrome b-245, beta polypeptide (chronic granulomatous disease)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1536.
- ↑ "NADPH oxidases in Eukaryotes: red algae provide new hints!". Current Genetics 49 (3): 190–204. March 2006. doi:10.1007/s00294-005-0044-z. PMID 16344959.
- ↑ "Molecular evolution of Phox-related regulatory subunits for NADPH oxidase enzymes". BMC Evolutionary Biology 7: 178. September 2007. doi:10.1186/1471-2148-7-178. PMID 17900370.
- ↑ 4.0 4.1 "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. doi:10.1016/j.freeradbiomed.2010.07.027. PMID 20696238.
- ↑ "Superoxide production and expression of nox family proteins in human atherosclerosis". Circulation 105 (12): 1429–1435. March 2002. doi:10.1161/01.cir.0000012917.74432.66. PMID 11914250.
- ↑ 6.0 6.1 "Nox2 is required for macrophage chemotaxis towards CSF-1". PLOS ONE 8 (2): e54869. 2013. doi:10.1371/journal.pone.0054869. PMID 23383302. Bibcode: 2013PLoSO...854869C.
- ↑ 7.0 7.1 "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. doi:10.1016/j.yjmcc.2013.09.007. PMID 24051369. https://www.openaccessrepository.it/record/22584.
- ↑ "The role of Nox2-derived ROS in the development of cognitive impairment after sepsis". Journal of Neuroinflammation 11 (1): 36. February 2014. doi:10.1186/1742-2094-11-36. PMID 24571599.
- ↑ "Endothelial Nox2 Limits Systemic Inflammation and Hypotension in Endotoxemia by Controlling Expression of Toll-Like Receptor 4". Shock 56 (2): 268–277. August 2021. doi:10.1097/SHK.0000000000001706. PMID 34276040.
- ↑ "Deficiency of Nox2 prevents angiotensin II-induced inward remodeling in cerebral arterioles". Frontiers in Physiology 4: 133. 26 June 2013. doi:10.3389/fphys.2013.00133. PMID 23805104.
- ↑ "CYBB cytochrome b-245 beta chain [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/1536.
- ↑ "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports 9 (1): 18577. December 2019. doi:10.1038/s41598-019-54976-4. PMID 31819097. Bibcode: 2019NatSR...918577S.
- ↑ "NOX2 up-regulation is associated with artery dysfunction in patients with peripheral artery disease". International Journal of Cardiology 165 (1): 184–192. April 2013. doi:10.1016/j.ijcard.2012.01.069. PMID 22336250.
- ↑ "Requirement of NOX2 expression in both retina and bone marrow for diabetes-induced retinal vascular injury". PLOS ONE 8 (12): e84357. 2013. doi:10.1371/journal.pone.0084357. PMID 24358357. Bibcode: 2013PLoSO...884357R.
- ↑ "Cigarette smoke alters the transcriptome of non-involved lung tissue in lung adenocarcinoma patients". Scientific Reports 9 (1): 13039. September 2019. doi:10.1038/s41598-019-49648-2. PMID 31506599. Bibcode: 2019NatSR...913039P.
- ↑ "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. doi:10.1152/ajpcell.00191.2013. PMID 23948707.
Further reading
- "Point mutations in the beta-subunit of cytochrome b558 leading to X-linked chronic granulomatous disease". Blood 77 (11): 2482–2487. June 1991. doi:10.1182/blood.V77.11.2482.2482. PMID 1710153.
- "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. doi:10.1016/0008-8749(91)90002-S. PMID 1905983.
- "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. doi:10.1172/JCI114898. PMID 2243141.
- "Cloning the gene for an inherited human disorder--chronic granulomatous disease--on the basis of its chromosomal location". Nature 322 (6074): 32–38. 1986. doi:10.1038/322032a0. PMID 2425263. Bibcode: 1986Natur.322...32R.
- "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. doi:10.1172/JCI114393. PMID 2556453.
- "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. doi:10.1038/327717a0. PMID 3600768. Bibcode: 1987Natur.327..717D.
- "The X-linked chronic granulomatous disease gene codes for the beta-chain of cytochrome b-245". Nature 327 (6124): 720–721. 1987. doi:10.1038/327720a0. PMID 3600769. Bibcode: 1987Natur.327..720T.
- "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. doi:10.1111/j.1600-0609.1993.tb00634.x. PMID 7694872.
- "Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production". Nature Genetics 9 (2): 202–209. February 1995. doi:10.1038/ng0295-202. PMID 7719350.
- "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. doi:10.1007/BF00201609. PMID 7927345.
- "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. doi:10.1073/pnas.91.22.10650. PMID 7938008. Bibcode: 1994PNAS...9110650L.
- "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. doi:10.1007/BF01955051. PMID 8101486.
- "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. doi:10.1172/JCI117207. PMID 8182143.
- "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. doi:10.1093/hmg/4.12.2339. PMID 8634708.
- "p40(phox) down-regulates NADPH oxidase activity through interactions with its SH3 domain". The Journal of Biological Chemistry 272 (14): 9141–9146. April 1997. doi:10.1074/jbc.272.14.9141. PMID 9083043.
- "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. doi:10.1074/jbc.272.14.9344. PMID 9083071.
- "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. doi:10.1111/j.1600-0609.1997.tb00928.x. PMID 9111587.
- "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. doi:10.1086/301874. PMID 9585602.
- "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. doi:10.1203/00006450-199807000-00014. PMID 9667376.
- "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. doi:10.1006/geno.1998.5510. PMID 9790760.
External links
- gp91phox+protein,+human at the US 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.
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