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Gene Review

CYBB  -  cytochrome b-245, beta polypeptide

Homo sapiens

Synonyms: AMCBX2, CGD, CGD91-phox, Cytochrome b(558) subunit beta, Cytochrome b-245 heavy chain, ...
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Disease relevance of CYBB


High impact information on CYBB

  • Together with the phagocyte NADPH oxidase itself (NOX2/gp91(phox)), the homologs are now referred to as the NOX family of NADPH oxidases [6].
  • Although insertional influences have probably reinforced the therapeutic efficacy in this trial, our results suggest that gene therapy in combination with bone marrow conditioning can be successfully used to treat inherited diseases affecting the myeloid compartment such as CGD [7].
  • The bacteriocidal capacity of phagocytic cells is impaired in X-linked chronic granulomatous disease (X-CGD), a disorder characterized by the absence of functional plasma-membrane-associated NADPH oxidase [8].
  • In Western blots antisera detect a neutrophil protein of relative molecular mass in 90,000 (90K) that is absent in X-CGD patients [8].
  • Based on our identification of the X-CGD protein in vivo, we propose that one of its critical roles is to interact with the 22K species to form a functional cytochrome b complex [8].

Chemical compound and disease context of CYBB


Biological context of CYBB


Anatomical context of CYBB

  • Improved superoxide-generating ability by interferon gamma due to splicing pattern change of transcripts in neutrophils from patients with a splice site mutation in CYBB gene [16].
  • Thus, this patient shows a somatic mosaic for the CYBB mutation, which probably originated during her lifetime in her bone marrow [14].
  • Moreover, the CYBB mutation was not present in the DNA from her cheek cells and was barely detectable in the DNA from her memory T lymphocytes [14].
  • The changes in the splicing pattern of the transcripts and the prolonged effect on superoxide-generating ability of patient neutrophils indicate that IFN-gamma induced a partial correction of the abnormal splicing of CYBB gene transcripts in myeloid progenitor cells [16].
  • The CYBB gene encodes gp91Phox; a component of the phagocyte respiratory burst oxidase [17].

Associations of CYBB with chemical compounds

  • In comparison to HoxA9, Nup98-hoxA9 has greater binding affinity for the CYBB cis element, but binding is not altered by HD tyrosine phosphorylation [17].
  • The X-linked form of the disease (X-CGD) arises from mutations in the CYBB gene, which encodes the 91-kD glycoprotein gp91(phox), the largest component of the oxidase [18].
  • This suggests that the alpha-helical loop of the C-terminal of Nox2 is probably involved in the correct assembly of the NADPH oxidase complex occurring during activation, permitting cytosolic factor translocation and electron transfer from NADPH to FAD [19].
  • We therefore conclude that the large subunit of the NADPH oxidase cytochrome b (gp91-phox) is the arachidonate activable H+ channel of human neutrophils [20].
  • In contrast, the D484T and D500A/R/G mutants of the alpha-helical loop of Nox2 exhibited no NADPH oxidase and INT reductase activities associated with a defective p47(phox) membrane translocation [19].

Physical interactions of CYBB

  • Thus, the introduction or reversal of charge at residues 369, 408, and 568 in gp91-phox destroys the correct binding of p47-phox and p67-phox to cytochrome b(558) [15].
  • We identify a sequence in the NCF2 promoter that is homologous to the HoxA10-binding CYBB cis element [21].
  • On the basis of these observations we propose that while Rac2 can bind to a site distinct from either gp91phox or p22phox, it depends upon an interaction with the flavocytochrome b558 for maximal stability in the membrane [22].
  • The mapping also confirmed a previously reported binding domain on gp91-phox (E554SGPRGVHFIF564) and putative Src homology 3 domain binding sites on p22-phox (P156PRPP160 and G177GPPGGP183) [23].
  • Finally, a new X91(+) CGD case was detected, characterized by a missense mutation Leu505Arg in the potential NADPH-binding site of gp91 phox [24].

Co-localisations of CYBB

  • In atherosclerotic arteries, there was an additional intense area of superoxide in the plaque shoulder, which is rich in macrophages and alpha-actin-positive cells. p22phox colocalized with gp91phox mainly in macrophages, whereas Nox4 was found only in nonphagocytic vascular cells [25].

Regulatory relationships of CYBB

  • Interestingly, NOX4 was expressed at 100-fold higher levels compared with NOX2 [26].
  • Previously, we identified a CYBB cis element, necessary for IFN-gamma-induced gp91phox expression, and also activated by this transcription factor combination [27].
  • In some rare cases, the mutated gp91 phox is normally expressed but no NADPH oxidase can be detected [28].
  • IQGAP1 regulates reactive oxygen species-dependent endothelial cell migration through interacting with Nox2 [29].
  • We reported that IQGAP1, an actin binding scaffold protein, mediates VEGF-induced activation of gp91phox (Nox2)-dependent NAD(P)H oxidase and EC migration [29].

Other interactions of CYBB


Analytical, diagnostic and therapeutic context of CYBB


  1. X-Linked chronic granulomatous disease: mutations in the CYBB gene encoding the gp91-phox component of respiratory-burst oxidase. Rae, J., Newburger, P.E., Dinauer, M.C., Noack, D., Hopkins, P.J., Kuruto, R., Curnutte, J.T. Am. J. Hum. Genet. (1998) [Pubmed]
  2. Interferon-gamma improves splicing efficiency of CYBB gene transcripts in an interferon-responsive variant of chronic granulomatous disease due to a splice site consensus region mutation. Condino-Neto, A., Newburger, P.E. Blood (2000) [Pubmed]
  3. Identification and characterization of TF1(phox), a DNA-binding protein that increases expression of gp91(phox) in PLB985 myeloid leukemia cells. Eklund, E.A., Kakar, R. J. Biol. Chem. (1997) [Pubmed]
  4. Impact of myeloperoxidase and NADPH-oxidase polymorphisms in drug-induced agranulocytosis. Mosyagin, I., Dettling, M., Roots, I., Mueller-Oerlinghausen, B., Cascorbi, I. Journal of clinical psychopharmacology. (2004) [Pubmed]
  5. Production of recombinant cytochrome b558 allows reconstitution of the phagocyte NADPH oxidase solely from recombinant proteins. Rotrosen, D., Yeung, C.L., Katkin, J.P. J. Biol. Chem. (1993) [Pubmed]
  6. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Bedard, K., Krause, K.H. Physiol. Rev. (2007) [Pubmed]
  7. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Ott, M.G., Schmidt, M., Schwarzwaelder, K., Stein, S., Siler, U., Koehl, U., Glimm, H., Kühlcke, K., Schilz, A., Kunkel, H., Naundorf, S., Brinkmann, A., Deichmann, A., Fischer, M., Ball, C., Pilz, I., Dunbar, C., Du, Y., Jenkins, N.A., Copeland, N.G., Lüthi, U., Hassan, M., Thrasher, A.J., Hoelzer, D., von Kalle, C., Seger, R., Grez, M. Nat. Med. (2006) [Pubmed]
  8. The glycoprotein encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex. Dinauer, M.C., Orkin, S.H., Brown, R., Jesaitis, A.J., Parkos, C.A. Nature (1987) [Pubmed]
  9. Somatic triple mosaicism in a carrier of X-linked chronic granulomatous disease. de Boer, M., Bakker, E., Van Lierde, S., Roos, D. Blood (1998) [Pubmed]
  10. A simple approach for the analysis of intracellular movement of oxidant-producing intracellular compartments in living human neutrophils. Kobayashi, T., Zinchuk, V.S., Okada, T., Wakiguchi, H., Kurashige, T., Takatsuji, H., Seguchi, H. Histochem. Cell Biol. (2000) [Pubmed]
  11. Intrapulmonary Mycobacterium avium infection as the first manifestation of chronic granulomatous disease. Ohga, S., Ikeuchi, K., Kadoya, R., Okada, K., Miyazaki, C., Suita, S., Ueda, K. J. Infect. (1997) [Pubmed]
  12. Nox2-containing NADPH oxidase and Akt activation play a key role in angiotensin II-induced cardiomyocyte hypertrophy. Hingtgen, S.D., Tian, X., Yang, J., Dunlay, S.M., Peek, A.S., Wu, Y., Sharma, R.V., Engelhardt, J.F., Davisson, R.L. Physiol. Genomics (2006) [Pubmed]
  13. Pholasin: a new chemiluminescent probe for the detection of chloramines derived from human phagocytes. Witko-Sarsat, V., Nguyen, A.T., Knight, J., Descamps-Latscha, B. Free Radic. Biol. Med. (1992) [Pubmed]
  14. Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB. Wolach, B., Scharf, Y., Gavrieli, R., de Boer, M., Roos, D. Blood (2005) [Pubmed]
  15. Four novel mutations in the gene encoding gp91-phox of human NADPH oxidase: consequences for oxidase assembly. Leusen, J.H., Meischl, C., Eppink, M.H., Hilarius, P.M., de Boer, M., Weening, R.S., Ahlin, A., Sanders, L., Goldblatt, D., Skopczynska, H., Bernatowska, E., Palmblad, J., Verhoeven, A.J., van Berkel, W.J., Roos, D. Blood (2000) [Pubmed]
  16. Improved superoxide-generating ability by interferon gamma due to splicing pattern change of transcripts in neutrophils from patients with a splice site mutation in CYBB gene. Ishibashi, F., Mizukami, T., Kanegasaki, S., Motoda, L., Kakinuma, R., Endo, F., Nunoi, H. Blood (2001) [Pubmed]
  17. HOXA9 activates transcription of the gene encoding gp91Phox during myeloid differentiation. Bei, L., Lu, Y., Eklund, E.A. J. Biol. Chem. (2005) [Pubmed]
  18. X-linked chronic granulomatous disease: first report of mutations in patients of Argentina. Barese, C., Copelli, S., Zandomeni, R., Oleastro, M., Zelazko, M., Rivas, E.M. J. Pediatr. Hematol. Oncol. (2004) [Pubmed]
  19. Crucial role of two potential cytosolic regions of Nox2, 191TSSTKTIRRS200 and 484DESQANHFAVHHDEEKD500, on NADPH oxidase activation. Li, X.J., Grunwald, D., Mathieu, J., Morel, F., Stasia, M.J. J. Biol. Chem. (2005) [Pubmed]
  20. The arachidonate-activable, NADPH oxidase-associated H+ channel. Evidence that gp91-phox functions as an essential part of the channel. Henderson, L.M., Banting, G., Chappell, J.B. J. Biol. Chem. (1995) [Pubmed]
  21. HoxA10 represses transcription of the gene encoding p67phox in phagocytic cells. Lindsey, S., Zhu, C., Lu, Y.F., Eklund, E.A. J. Immunol. (2005) [Pubmed]
  22. Rac translocates independently of the neutrophil NADPH oxidase components p47phox and p67phox. Evidence for its interaction with flavocytochrome b558. Heyworth, P.G., Bohl, B.P., Bokoch, G.M., Curnutte, J.T. J. Biol. Chem. (1994) [Pubmed]
  23. Mapping sites of interaction of p47-phox and flavocytochrome b with random-sequence peptide phage display libraries. DeLeo, F.R., Yu, L., Burritt, J.B., Loetterle, L.R., Bond, C.W., Jesaitis, A.J., Quinn, M.T. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  24. Characterization of six novel mutations in the CYBB gene leading to different sub-types of X-linked chronic granulomatous disease. Stasia, M.J., Bordigoni, P., Floret, D., Brion, J.P., Bost-Bru, C., Michel, G., Gatel, P., Durant-Vital, D., Voelckel, M.A., Li, X.J., Guillot, M., Maquet, E., Martel, C., Morel, F. Hum. Genet. (2005) [Pubmed]
  25. Superoxide production and expression of nox family proteins in human atherosclerosis. Sorescu, D., Weiss, D., Lassègue, B., Clempus, R.E., Szöcs, K., Sorescu, G.P., Valppu, L., Quinn, M.T., Lambeth, J.D., Vega, J.D., Taylor, W.R., Griendling, K.K. Circulation (2002) [Pubmed]
  26. Expression and localization of NOX2 and NOX4 in primary human endothelial cells. Van Buul, J.D., Fernandez-Borja, M., Anthony, E.C., Hordijk, P.L. Antioxid. Redox Signal. (2005) [Pubmed]
  27. Recruitment of CREB-binding protein by PU.1, IFN-regulatory factor-1, and the IFN consensus sequence-binding protein is necessary for IFN-gamma-induced p67phox and gp91phox expression. Eklund, E.A., Kakar, R. J. Immunol. (1999) [Pubmed]
  28. Functional analysis of two-amino acid substitutions in gp91 phox in a patient with X-linked flavocytochrome b558-positive chronic granulomatous disease by means of transgenic PLB-985 cells. Bionda, C., Li, X.J., van Bruggen, R., Eppink, M., Roos, D., Morel, F., Stasia, M.J. Hum. Genet. (2004) [Pubmed]
  29. IQGAP1 regulates reactive oxygen species-dependent endothelial cell migration through interacting with Nox2. Ikeda, S., Yamaoka-Tojo, M., Hilenski, L., Patrushev, N.A., Anwar, G.M., Quinn, M.T., Ushio-Fukai, M. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  30. 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. Leusen, J.H., de Boer, M., Bolscher, B.G., Hilarius, P.M., Weening, R.S., Ochs, H.D., Roos, D., Verhoeven, A.J. J. Clin. Invest. (1994) [Pubmed]
  31. Del(X)(p21.1) in a mother and two daughters: genotype-phenotype correlation of Turner features. Adachi, M., Tachibana, K., Asakura, Y., Muroya, K., Ogata, T. Hum. Genet. (2000) [Pubmed]
  32. Linkage analysis in a large Spanish family with X-linked retinitis pigmentosa: phenotype-genotype correlation. Capeans, C., Blanco, M.J., Lareu, M.V., Barros, F., Piñeiro, A., Sanchez-Salorio, M., Carracedo, A. Clin. Genet. (1998) [Pubmed]
  33. Regulation of superoxide-producing NADPH oxidases in nonphagocytic cells. Takeya, R., Ueno, N., Sumimoto, H. Meth. Enzymol. (2006) [Pubmed]
  34. Diagnostic paradigm for evaluation of male patients with chronic granulomatous disease, based on the dihydrorhodamine 123 assay. Jirapongsananuruk, O., Malech, H.L., Kuhns, D.B., Niemela, J.E., Brown, M.R., Anderson-Cohen, M., Fleisher, T.A. J. Allergy Clin. Immunol. (2003) [Pubmed]
  35. 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. Ariga, T., Sakiyama, Y., Tomizawa, K., Imajoh-Ohmi, S., Kanegasaki, S., Matsumoto, S. Eur. J. Pediatr. (1993) [Pubmed]
  36. Long polymerase chain reaction-based fluorescence in situ hybridization analysis of female carriers of X-linked chronic granulomatous disease deletions. Simon, K.C., Noack, D., Rae, J., Curnutte, J., Sarraf, S., Kolev, V., Blancato, J.K. The Journal of molecular diagnostics : JMD. (2005) [Pubmed]
  37. The molecular basis of chronic granulomatous disease. Meischl, C., Roos, D. Springer Semin. Immunopathol. (1998) [Pubmed]
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