Interferon 8 regulatory factor (IRF8) also known as interferon consensus protein (ICSBP), a protein that is encoded in humans by the IRF8 gene . [1] [2] [3] IRF8 is a transcription factor that has several important functions in the regulation of committing and in cell maturation, including the common myeloid precursor (CMP), in order to differentiate progenitor cells into monocytes .
| Interferon regulatory factor 8 | |||||||||||||
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| Symbol | ; H-ICSBP; ICSBP; ICSBP1; IRF-8 | ||||||||||||
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Function
The Interferon Consensus Serial Binding Protein (ICSBP) is a transcription factor in the family of regulatory interferon factors (IRF). The proteins of this family consist of a conserved DNA binding domain in the and a diverging region, which serves as a regulatory domain. In the IRF family, proteins bind to IFN-stimulated response elements (ISREs) and regulate the expression of genes stimulated by type I interferon, namely IFN-α and IFN-β. Proteins of the IRF family also control the expression of IFN-α and IFN-β-regulatory genes, which is caused by a viral infection. [one]
Knockout Research
IFN-producing cells (mIPCs) were absent in all lymphoid organs in ICSBP knockout (KO) mice, and the absence of CD11c low B220 + Ly6C + CD11b cells was also detected. In parallel, CD11c + cells isolated from ICSBP KO spleen were unable to produce type I interferons in response to viral stimulation. ICSBP KO mice also showed a marked reduction in a subset of dendritic cells (DC) expressing the CD8alpha marker (CD8alpha + DCs) in the spleen, lymph nodes and thymus gland. In addition, a markedly attenuated phenotype is presented in ICSBP-deficient CD8alpha + DC compared to WT DC. They expressed very low levels of co-stimulatory molecules (cell-cell adhesion ICAM1 , CD40 , CD80 , CD86 ) and T-cell areaoming of CCR7 chemokine receptor. [four]
Clinical Importance
In myeloid cells, IRF8 regulates the expression of Bax and Fas to regulate apoptosis . [5] In chronic myeloid leukemia (CML), IRF8 regulates CML apoptosis with acid as an intermediary. [6]
IRF8 is highly expressed in myeloid cells, and was originally identified as a critical linear-specific transcription factor for the differentiation of myeloid cells. [7] Recent studies, however, have shown that IRF8 is also expressed in non- hematopoietic cancer cells, albeit at a low level. In addition, IRF8 can also be further regulated by IFN-γ in non-hematopoietic cells. IRF8 mediates the expression of Fas, Bax, , JAK1 and STAT1 to mediate apoptosis in non-blood-forming cancer cells. [8] [9] [10]
Analysis of the human cancer genomic data base showed that IRF8 does not significantly increase over the entire data set of more than 3 thousand tumors, but was significantly reduced in them, therefore, it is assumed that IRF8 is a potential tumor suppressor in the human body. [11] Molecular analysis showed that the IRF8 promoter gene is hypermethylated into human colon cell carcinomas , [10] [12] indicating that these cells can use DNA methylation to suppress the expression of IRF8 to advance the disease.
Interactions
IRF8 has been found to interact with IRF1 [13] [14] and COPS2 . [15]
See also
- Interferon
- IRF1 , IRF2 , IRF3 , IRF4 , IRF5 , IRF6 , IRF7 , IRF8 and IRF9
Notes
- ↑ 1 2 Entrez Gene: IRF8 interferon regulatory factor 8 .
- ↑ 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 (English) / / J. Biol. Chem. : journal. - 1992 .-- December ( vol. 267 , no. 35 ). - P. 25589-25596 . - PMID 1460054 .
- ↑ 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 (English) // Mol. Cell. Biol. : journal. - 2002 .-- June ( vol. 22 , no. 11 ). - P. 3942-3957 . - DOI : 10.1128 / MCB.22.11.3942-3957.2002 . - PMID 11997525 .
- ↑ Tamura T., Ozato K. ICSBP / IRF-8: its regulatory roles in the development of myeloid cells (Eng.) // J. Interferon Cytokine Res. : journal. - 2002 .-- January ( vol. 22 , no. 1 ). - P. 145-152 . - DOI : 10.1089 / 107999002753452755 . - PMID 11846985 .
- ↑ 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 (Eng.) // J. Immunol. : journal. - 2011 .-- November ( vol. 187 , no. 9 ). - P. 4426-4430 . - DOI : 10.4049 / jimmunol . 1101034 . - PMID 21949018 .
- ↑ 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 (English) // Cancer Res. : journal. - 2011 .-- April ( vol. 71 , no. 8 ). - P. 2882-2881 . - DOI : 10.1158 / 0008-5472.CAN-10-2493 . - PMID 21487040 .
- ↑ 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 (Eng.) // Cell : journal. - Cell Press 1996. - October ( vol. 87 , no. 2 ). - P. 307-317 . - DOI : 10.1016 / S0092-8674 (00) 81348-3 . - PMID 8861914 .
- ↑ 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. : journal. - 2009 .-- February ( vol. 69 , no. 3 ). - P. 1080-1088 . - DOI : 10.1158 / 0008-5472.CAN-08-2520 . - PMID 19155307 .
- ↑ 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. : journal. - 2007 .-- October ( vol. 179 , no. 7 ). - P. 4775-4782 . - DOI : 10.4049 / jimmunol . 179.7.4775 . - PMID 17878376 .
- ↑ 1 2 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 (English) // Cancer Res. : journal. - 2007 .-- April ( vol. 67 , no. 7 ). - P. 3301-3309 . - DOI : 10.1158 / 0008-5472.CAN-06-4068 . - PMID 17409439 .
- ↑ Tumorscape unopened (inaccessible link) . The Broad Institute. Date of treatment March 21, 2015. Archived on April 14, 2012.
- ↑ 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 (Eng.) // Mol. Cancer Res. : journal. - 2008 .-- December ( vol. 6 , no. 12 ). - P. 1841-1851 . - DOI : 10.1158 / 1541-7786.MCR-08-0280 . - PMID 19074829 .
- ↑ 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. : journal. - 1998 .-- October ( vol. 335 , no. 1 ). - P. 147-157 . - PMID 9742224 .
- ↑ 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 (Eng.) // J. Biol . Chem. : journal. - 1995 .-- June ( vol. 270 , no. 22 ). - P. 13063-13069 . - DOI : 10.1074 / jbc.270.22.13063 . - PMID 7768900 .
- ↑ 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. : journal. - 2000 .-- December ( vol. 275 , no. 50 ). - P. 39081-39089 . - DOI : 10.1074 / jbc.M004900200 . - PMID 10991940 .
Literature
- 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. (English) // J. Biol. Chem. : journal. - 1993. - Vol. 267 , no. 35 . - P. 25589-25596 . - PMID 1460054 .
- 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. (English) // J. Biol. Chem. : journal. - 1995. - Vol. 270 , no. 22 . - P. 13063-13069 . - DOI : 10.1074 / jbc.270.22.13063 . - PMID 7768900 .
- 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. (English) // Cell : journal. - Cell Press 1996. - Vol. 87 , no. 2 . - P. 307-317 . - DOI : 10.1016 / S0092-8674 (00) 81348-3 . - PMID 8861914 .
- 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). (English) // Biochem. J. : journal. - 1998. - Vol. 335 , no. 1 . - P. 147-157 . - PMID 9742224 .
- 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. (English) // J. Biol. Chem. : journal. - 1999. - Vol. 274 , no. 14 . - P. 9686-9691 . - DOI : 10.1074 / jbc.274.14.9686 . - PMID 10092656 .
- 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. (Eng.) // Invest. Ophthalmol. Vis Sci. : journal. - 1999. - Vol. 40 , no. 5 . - P. 976-982 . - PMID 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. (English) // J. Biol. Chem. : journal. - 2000. - Vol. 275 , no. 13 . - P. 9773-9781 . - DOI : 10.1074 / jbc.275.13.9773 . - PMID 10734131 .
- 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. (English) // J. Biol. Chem. : journal. - 2001. - Vol. 275 , no. 50 . - P. 39081-39089 . - DOI : 10.1074 / jbc.M004900200 . - PMID 10991940 .
- 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. (English) // Mol. Cell. Biol. : journal. - 2002. - Vol. 22 , no. 11 . - P. 3942-3957 . - DOI : 10.1128 / MCB.22.11.3942-3957.2002 . - PMID 11997525 .
- Zhu C., Saberwal G., Lu Y., Platanias LC, Eklund EA The interferon consensus sequence-binding protein activates transcription of the gene encoding neurofibromin 1. (Eng.) // J. Biol. Chem. : journal. - 2005. - Vol. 279 , no. 49 . - P. 50874-50885 . - DOI : 10.1074 / jbc.M405736200 . - PMID 15371411 .
- 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. (English) // J. Biol. Chem. : journal. - 2005. - Vol. 279 , no. 53 . - P. 55609–55617 . - DOI : 10.1074 / jbc.M406565200 . - PMID 15489234 .
- 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. (English) // Science: journal. - 2005. - Vol. 307 , no. 5715 . - P. 1621-1625 . - DOI : 10.1126 / science.1105776 . - PMID 15761153 .
- 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. (English) // J. Biol. Chem. : journal. - 2005. - Vol. 280 , no. 25 . - P. 23531-23539 . - DOI : 10.1074 / jbc.M414296200 . - PMID 15837792 .
- 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. (English) // J. Biol. Chem. : journal. - 2006. - Vol. 281 , no. 15 . - P. 10073-10080 . - DOI : 10.1074 / jbc.M507788200 . - PMID 16484229 .
- 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. (English) // Mol. Cell. Biol. : journal. - 2006. - Vol. 26 , no. 17 . - P. 6311-6332 . - DOI : 10.1128 / MCB.00036-06 . - PMID 16914719 .
- 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. (English) // Scand. J. Immunol. : journal. - 2006. - Vol. 64 , no. 3 . - P. 271—279 . - DOI : 10.1111 / j.1365-3083.2006.01827.x . - PMID 16918696 .
- 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 // Eng. Cardiovasc. Genet. May 9. [Epub ahead of print]: journal. - 2013 .-- Vol. 6 , no. 3 . - P. 255-263 . - DOI : 10.1161 / CIRCGENETICS.113.000044 . - PMID 23661672 .
- Peng YB, Yerle M., Liu B. Mapping of nine porcine interferon regulatory factor genes. (Eng.) // Anim. Genet. : journal. - 2007. - Vol. 37 , no. 6 . - P. 600-601 . - DOI : 10.1111 / j.1365-2052.2006.01525.x . - PMID 17121613 .
- 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. (English) // J. Biol. Chem. : journal. - 2007. - Vol. 282 , no. 9 . - P. 6629-6643 . - DOI : 10.1074 / jbc.M607760200 . - PMID 17200120 .
- 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. (Eng.) // Blood : journal. - American Society of Hematology , 2006. - Vol. 108 , no. 2 . - P. 609-617 . - DOI : 10.1182 / blood-2005-11-4490 . - PMID 16569763 .
- 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. (English) // Journal of Experimental Medicine : journal. - Rockefeller University Press , 2002. - Vol. 196 , no. 11 . - P. 1415-1425 . - DOI : 10.1084 / jem.20021263 . - PMID 12461077 .
Interferon regulatory factors