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 NOX2gene (also called CYBB gene).[5] 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.[6] 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.[7] 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.[8]
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.[11]
Furthermore, it increases global post-reperfusion oxidative stress, likely due to decreased
STAT3 and
Erk phosphorylation.[11]
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).[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 in
angiotensin II-mediated inward remodelling in cerebral arterioles due to the emittance of superoxides from Nox2-containing
NADPH oxidases.[14]
Clinical significance
CYBB deficiency is one of five described biochemical defects associated with
chronic granulomatous disease (CGD).[15] 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. [8] 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.[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 a
myocardial 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 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.[18]
CYBB transcript levels are upregulated in the lung parenchyma of smokers. [19]
Interactions
Nox2 has been shown to interact directly with
podocyte TRPC6 channels.[20]
^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.
^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.
^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.
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, 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.
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.
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.
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.
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.