IRF8 explained

Interferon regulatory factor 8 (IRF8) also known as interferon consensus sequence-binding protein (ICSBP), is a protein that in humans is encoded by the IRF8 gene.^{[1] [2] [3]} IRF8 is a transcription factor that plays critical roles in the regulation of lineage commitment and in myeloid cell maturation including the decision for a common myeloid progenitor (CMP) to differentiate into a monocyte precursor cell.

Function

Interferon Consensus Sequence-binding protein (ICSBP) is a transcription factor of the interferon regulatory factor (IRF) family. Proteins of this family are composed of a conserved DNA-binding domain in the N-terminal region and a divergent C-terminal region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulated response element (ISRE) and regulate expression of genes stimulated by type I IFNs, namely IFN-α and IFN-β. IRF family proteins also control expression of IFN-α and IFN-β-regulated genes that are induced by viral infection.^[1]

Knockout studies

IFN-producing cells (mIPCs) were absent in all lymphoid organs from ICSBP knockout (KO) mice, as revealed by lack of CD11c^lowB220⁺Ly6C⁺CD11b⁻ cells. In parallel, CD11c⁺ cells isolated from ICSBP KO spleens were unable to produce type I IFNs in response to viral stimulation. ICSBP KO mice also displayed a marked reduction of the DC subset expressing the CD8alpha marker (CD8alpha⁺ DCs) in spleen, lymph nodes, and thymus. Moreover, ICSBP-deficient CD8alpha⁺ DCs exhibited a markedly impaired phenotype when compared with WT DCs. They expressed very low levels of costimulatory molecules (intercellular adhesion molecule ICAM1, CD40, CD80, CD86) and of the T cell area-homing chemokine receptor CCR7.^[4]

Clinical significance

In myeloid cells, IRF8 regulates the expression of Bax and Fas to regulate apoptosis.^[5] In chronic myelogenous leukemia (CML), IRF8 regulates acid ceramidase to mediate CML apoptosis.^[6]

IRF8 is highly expressed in myeloid cells and was originally identified in as a critical lineage-specific transcription factor for myeloid cell differentiation,^[7] recent studies, however, have shown that IRF8 is also constitutively expressed in non-hematopoietic cancer cells, albeit at a lower level. Furthermore, IRF8 can also be up-regulated by IFN-γ in non-hemotopoietic cells. IRF8 mediates the expression of Fas, Bax, FLIP, Jak1 and STAT1 to mediate apoptosis in non-hemotopoietic cancer cells.^{[8] [9] [10]}

Analysis of human cancer genomics database revealed that IRF8 is not significantly focally amplified across the entire dataset of 3131 tumors, but is significantly focally deleted across the entire dataset of 3131 tumors, suggesting that IRF8 is potentially a tumor suppressor in humans.^[11] Molecular analysis indicated that the IRF8 gene promoter is hypermethylated in human colon carcinoma cells,^{[10] [12]} suggesting that these cells might use DNA methylation to silence IRF8 expression to advance the disease.

Interactions

IRF8 has been shown to interact with IRF1^{[13] [14]} and COPS2.^[15]

See also

• Interferon regulatory factors

Further reading

• Weisz A, Marx P, Sharf R, Appella E, Driggers PH, Ozato K, Levi BZ . Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes. . J. Biol. Chem. . 267 . 35 . 25589–96 . 1993 . 10.1016/S0021-9258(19)74081-2 . 1460054 . free .
• Sharf R, Azriel A, Lejbkowicz F, Winograd SS, Ehrlich R, Levi BZ . Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors. . J. Biol. Chem. . 270 . 22 . 13063–9 . 1995 . 7768900 . 10.1074/jbc.270.22.13063 . free .
• Holtschke T, Löhler J, Kanno Y, Fehr T, Giese N, Rosenbauer F, Lou J, Knobeloch KP, Gabriele L, Waring JF, Bachmann MF, Zinkernagel RM, Morse HC, Ozato K, Horak I . Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. . Cell . 87 . 2 . 307–17 . 1996 . 8861914 . 10.1016/S0092-8674(00)81348-3 . 18065448 . free .
• Schaper F, Kirchhoff S, Posern G, Köster M, Oumard A, Sharf R, Levi BZ, Hauser H . Functional domains of interferon regulatory factor I (IRF-1). . Biochem. J. . 335 . 1 . 147–57 . 1998 . 9742224 . 1219763 . 10.1042/bj3350147.
• Li W, Nagineni CN, Ge H, Efiok B, Chepelinsky AB, Egwuagu CE . Interferon consensus sequence-binding protein is constitutively expressed and differentially regulated in the ocular lens. . J. Biol. Chem. . 274 . 14 . 9686–91 . 1999 . 10092656 . 10.1074/jbc.274.14.9686 . free .
• Li W, Nagineni CN, Hooks JJ, Chepelinsky AB, Egwuagu CE . Interferon-gamma signaling in human retinal pigment epithelial cells mediated by STAT1, ICSBP, and IRF-1 transcription factors. . Invest. Ophthalmol. Vis. Sci. . 40 . 5 . 976–82 . 1999 . 10102295 .
• Rehli M, Poltorak A, Schwarzfischer L, Krause SW, Andreesen R, Beutler B . PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human Toll-like receptor 4 gene. . J. Biol. Chem. . 275 . 13 . 9773–81 . 2000 . 10734131 . 10.1074/jbc.275.13.9773 . free .
• Cohen H, Azriel A, Cohen T, Meraro D, Hashmueli S, Bech-Otschir D, Kraft R, Dubiel W, Levi BZ . Interaction between interferon consensus sequence-binding protein and COP9/signalosome subunit CSN2 (Trip15). A possible link between interferon regulatory factor signaling and the COP9/signalosome. . J. Biol. Chem. . 275 . 50 . 39081–9 . 2001 . 10991940 . 10.1074/jbc.M004900200 . free .
• Nehyba J, Hrdlicková R, Burnside J, Bose HR . A novel interferon regulatory factor (IRF), IRF-10, has a unique role in immune defense and is induced by the v-Rel oncoprotein. . Mol. Cell. Biol. . 22 . 11 . 3942–57 . 2002 . 11997525 . 133824 . 10.1128/MCB.22.11.3942-3957.2002 .
• Zhu C, Saberwal G, Lu Y, Platanias LC, Eklund EA . The interferon consensus sequence-binding protein activates transcription of the gene encoding neurofibromin 1. . J. Biol. Chem. . 279 . 49 . 50874–85 . 2005 . 15371411 . 10.1074/jbc.M405736200 . free .
• Liu J, Guan X, Tamura T, Ozato K, Ma X . Synergistic activation of interleukin-12 p35 gene transcription by interferon regulatory factor-1 and interferon consensus sequence-binding protein. . J. Biol. Chem. . 279 . 53 . 55609–17 . 2005 . 15489234 . 10.1074/jbc.M406565200 . free .
• Barrios-Rodiles M, Brown KR, Ozdamar B, Bose R, Liu Z, Donovan RS, Shinjo F, Liu Y, Dembowy J, Taylor IW, Luga V, Przulj N, Robinson M, Suzuki H, Hayashizaki Y, Jurisica I, Wrana JL . High-throughput mapping of a dynamic signaling network in mammalian cells. . Science . 307 . 5715 . 1621–5 . 2005 . 15761153 . 10.1126/science.1105776 . 2005Sci...307.1621B . 39457788 .
• Xiong H, Li H, Kong HJ, Chen Y, Zhao J, Xiong S, Huang B, Gu H, Mayer L, Ozato K, Unkeless JC . Ubiquitin-dependent degradation of interferon regulatory factor-8 mediated by Cbl down-regulates interleukin-12 expression. . J. Biol. Chem. . 280 . 25 . 23531–9 . 2005 . 15837792 . 10.1074/jbc.M414296200 . free .
• Zhao J, Kong HJ, Li H, Huang B, Yang M, Zhu C, Bogunovic M, Zheng F, Mayer L, Ozato K, Unkeless J, Xiong H . IRF-8/interferon (IFN) consensus sequence-binding protein is involved in Toll-like receptor (TLR) signaling and contributes to the cross-talk between TLR and IFN-gamma signaling pathways. . J. Biol. Chem. . 281 . 15 . 10073–80 . 2006 . 16484229 . 10.1074/jbc.M507788200 . free .
• Huang W, Saberwal G, Horvath E, Zhu C, Lindsey S, Eklund EA . Leukemia-associated, constitutively active mutants of SHP2 protein tyrosine phosphatase inhibit NF1 transcriptional activation by the interferon consensus sequence binding protein. . Mol. Cell. Biol. . 26 . 17 . 6311–32 . 2006 . 16914719 . 1592828 . 10.1128/MCB.00036-06 .
• Dimberg A, Kårehed K, Nilsson K, Oberg F . Inhibition of monocytic differentiation by phosphorylation-deficient Stat1 is associated with impaired expression of Stat2, ICSBP/IRF8 and C/EBPepsilon. . Scand. J. Immunol. . 64 . 3 . 271–9 . 2006 . 16918696 . 10.1111/j.1365-3083.2006.01827.x . 22527134 .
• Leonard D, Svenungsson E, Sandling JK, Berggren O, Jönsen A, Bengtsson C, Wang C, Jensen-Urstad K, Granstam SO, Bengtsson AA, Gustafsson JT, Gunnarsson I, Rantapää-Dahlqvist S, Nordmark G, Eloranta ML, Syvänen AC, Rönnblom L . Coronary Heart Disease in Systemic Lupus Erythematosus Is Associated with Interferon Regulatory Factor 8 Gene Variants . Circ. Cardiovasc. Genet. . 6 . 3 . 255–63 . 2013 . 23661672 . 10.1161/CIRCGENETICS.113.000044 . free .
• Peng YB, Yerle M, Liu B . Mapping of nine porcine interferon regulatory factor genes. . Anim. Genet. . 37 . 6 . 600–1 . 2007 . 17121613 . 10.1111/j.1365-2052.2006.01525.x .
• Huang W, Horvath E, Eklund EA . PU.1, interferon regulatory factor (IRF) 2, and the interferon consensus sequence-binding protein (ICSBP/IRF8) cooperate to activate NF1 transcription in differentiating myeloid cells. . J. Biol. Chem. . 282 . 9 . 6629–43 . 2007 . 17200120 . 10.1074/jbc.M607760200 . free .
• Mattei F, Schiavoni G, Borghi P, Venditti M, Canini I, Sestili P, Pietraforte I, Morse HC, Ramoni C, Belardelli F, Gabriele L . ICSBP/IRF-8 differentially regulates antigen uptake during dendritic-cell development and affects antigen presentation to CD4+ T cells. . Blood . 108 . 2 . 609–617 . 2006 . 16569763 . 10.1182/blood-2005-11-4490 . free .
• Schiavoni G, Mattei F, Sestili P, Borghi P, Venditti M, Morse HC, Belardelli F, Gabriele L . ICSBP is essential for the development of mouse type I interferon-producing cells and for the generation and activation of CD8alpha(+) dendritic cells. . J. Exp. Med. . 196 . 11 . 1415–1425 . 2002 . 12461077 . 2194263 . 10.1084/jem.20021263 .

Notes and References

1. Web site: Entrez Gene: IRF8 interferon regulatory factor 8.
2. Weisz A, Marx P, Sharf R, Appella E, Driggers PH, Ozato K, Levi BZ . Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes . J. Biol. Chem. . 267 . 35 . 25589–96 . December 1992 . 10.1016/S0021-9258(19)74081-2 . 1460054 . free .
3. Nehyba J, Hrdlicková R, Burnside J, Bose HR . A novel interferon regulatory factor (IRF), IRF-10, has a unique role in immune defense and is induced by the v-Rel oncoprotein . Mol. Cell. Biol. . 22 . 11 . 3942–57 . June 2002 . 11997525 . 133824 . 10.1128/MCB.22.11.3942-3957.2002 .
4. Tamura T, Ozato K . ICSBP/IRF-8: its regulatory roles in the development of myeloid cells . J. Interferon Cytokine Res. . 22 . 1 . 145–52 . January 2002 . 11846985 . 10.1089/107999002753452755 .
5. Yang J, Hu X, Zimmerman M, Torres CM, Yang D, Smith SB, Liu K . Cutting edge: IRF8 regulates Bax transcription in vivo in primary myeloid cells . J. Immunol. . 187 . 9 . 4426–30 . November 2011 . 21949018 . 3197864 . 10.4049/jimmunol.1101034 .
6. Hu X, Yang D, Zimmerman M, Liu F, Yang J, Kannan S, Burchert A, Szulc Z, Bielawska A, Ozato K, Bhalla K, Liu K . IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia . Cancer Res. . 71 . 8 . 2882–91 . April 2011 . 21487040 . 3078194 . 10.1158/0008-5472.CAN-10-2493 .
7. Holtschke T, Löhler J, Kanno Y, Fehr T, Giese N, Rosenbauer F, Lou J, Knobeloch KP, Gabriele L, Waring JF, Bachmann MF, Zinkernagel RM, Morse HC, Ozato K, Horak I . Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene . Cell . 87 . 2 . 307–17 . October 1996 . 8861914 . 10.1016/S0092-8674(00)81348-3 . 18065448 . free .
8. Yang D, Wang S, Brooks C, Dong Z, Schoenlein PV, Kumar V, Ouyang X, Xiong H, Lahat G, Hayes-Jordan A, Lazar A, Pollock R, Lev D, Liu K . IFN regulatory factor 8 sensitizes soft tissue sarcoma cells to death receptor-initiated apoptosis via repression of FLICE-like protein expression . Cancer Res. . 69 . 3 . 1080–8 . February 2009 . 19155307 . 2633427 . 10.1158/0008-5472.CAN-08-2520 .
9. Yang D, Thangaraju M, Browning DD, Dong Z, Korchin B, Lev DC, Ganapathy V, Liu K . IFN regulatory factor 8 mediates apoptosis in nonhemopoietic tumor cells via regulation of Fas expression . J. Immunol. . 179 . 7 . 4775–82 . October 2007 . 17878376 . 10.4049/jimmunol.179.7.4775 . free .
10. Yang D, Thangaraju M, Greeneltch K, Browning DD, Schoenlein PV, Tamura T, Ozato K, Ganapathy V, Abrams SI, Liu K . Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells . Cancer Res. . 67 . 7 . 3301–9 . April 2007 . 17409439 . 10.1158/0008-5472.CAN-06-4068 .
11. Web site: Tumorscape . The Broad Institute . 2012-07-05 . https://web.archive.org/web/20120414021752/http://www.broadinstitute.org/tumorscape/pages/portalHome.jsf . 2012-04-14 . dead .
12. McGough JM, Yang D, Huang S, Georgi D, Hewitt SM, Röcken C, Tänzer M, Ebert MP, Liu K . DNA methylation represses IFN-gamma-induced and signal transducer and activator of transcription 1-mediated IFN regulatory factor 8 activation in colon carcinoma cells . Mol. Cancer Res. . 6 . 12 . 1841–51 . December 2008 . 19074829 . 2605678 . 10.1158/1541-7786.MCR-08-0280 .
13. Schaper F, Kirchhoff S, Posern G, Köster M, Oumard A, Sharf R, Levi BZ, Hauser H . Functional domains of interferon regulatory factor I (IRF-1) . Biochem. J. . 335 . 1 . 147–57 . October 1998 . 9742224 . 1219763 . 10.1042/bj3350147.
14. Sharf R, Azriel A, Lejbkowicz F, Winograd SS, Ehrlich R, Levi BZ . Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors . J. Biol. Chem. . 270 . 22 . 13063–9 . June 1995 . 7768900 . 10.1074/jbc.270.22.13063 . free .
15. Cohen H, Azriel A, Cohen T, Meraro D, Hashmueli S, Bech-Otschir D, Kraft R, Dubiel W, Levi BZ . Interaction between interferon consensus sequence-binding protein and COP9/signalosome subunit CSN2 (Trip15). A possible link between interferon regulatory factor signaling and the COP9/signalosome . J. Biol. Chem. . 275 . 50 . 39081–9 . December 2000 . 10991940 . 10.1074/jbc.M004900200 . free .