CYBB

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Cytochrome b-245 heavy chain also known as cytochrome b(558) subunit beta or NADPH oxidase 2 or Nox2 is a protein that in humans is encoded by the CYBB gene.[1] The protein is a super-oxide generating enzyme which forms reactive oxygen species (ROS).

Function

Nox2, or Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes.[1]

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]

There has been recent evidence that it plays an important role in atherosclerotic lesion development in the aortic arch, thoracic, and abdominal aorta.[5]

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.[6] Furthermore, it increases global post-reperfusion oxidative stress, likely due to decreased STAT3 and Erk phosphorylation.[6]

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).[7]

Lastly, due to recent experiments, 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.[8]

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. [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]

Since Nox2 was shown to play a huge part in determining the size of a myocardial infarction, this transforms the protein into a possible future target through 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.[9]

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.[10]

Interactions

Nox2 has been shown to interact directly with podocyte TRPC6 channels.[11]

References

  1. 1.0 1.1 1.2 "Entrez Gene: CYBB cytochrome b-245, beta polypeptide (chronic granulomatous disease)".
  2. 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. PMID 16344959.
  3. Kawahara T, Lambeth JD (September 2007). "Molecular evolution of Phox-related regulatory subunits for NADPH oxidase enzymes". BMC Evolutionary Biology. 7: 178. doi:10.1186/1471-2148-7-178. PMID 17900370.
  4. 4.0 4.1 Aguirre, Jesús; Lambeth, J (2010). "Nox enzymes from fungus to fly to fish and what they tell us about Nox function in mammals". Free Radical Biology and Medicine. 49: 1342–1353.
  5. "Nox2 is required for macrophage chemotaxis towards CSF-1". PMID 23383302.
  6. 6.0 6.1 6.2 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 (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. PMID 24051369.
  7. Hernandes MS, D'Avila JC, Trevelin SC, Reis PA, Kinjo ER, Lopes LR, Castro-Faria-Neto HC, Cunha FQ, Britto LR, Bozza FA (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. PMC 3974031. PMID 24571599.
  8. 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. PMC 3693079. PMID 23805104.
  9. 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 (April 2013). "NOX2 up-regulation is associated with artery dysfunction in patients with peripheral artery disease". International Journal of Cardiology. 165 (1): 184–92. doi:10.1016/j.ijcard.2012.01.069. PMID 22336250.
  10. "Requirement of NOX2 Expression in Both Retina and Bone Marrow for Diabetes-Induced Retinal Vascular Injury".
  11. 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): C960–71. doi:10.1152/ajpcell.00191.2013. PMID 23948707.

Further reading

External links