Protein-coding gene in the species Homo sapiens
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 .
[5]
[6]
[7] 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.
[5]
Knockout studies
IFN-producing cells (mIPCs) were absent in all lymphoid organs from ICSBP
knockout (KO) mice, as revealed by lack of CD11clow B220+ 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 .
[8]
Clinical significance
In myeloid cells, IRF8 regulates the expression of
Bax and
Fas to regulate
apoptosis .
[9] In
chronic myelogenous leukemia (CML), IRF8 regulates acid
ceramidase to mediate CML apoptosis.
[10]
IRF8 is highly expressed in myeloid cells and was originally identified in as a critical lineage-specific transcription factor for myeloid cell differentiation,
[11] 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.
[12]
[13]
[14]
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.
[15] Molecular analysis indicated that the IRF8 gene promoter is hypermethylated in human
colon carcinoma cells,
[14]
[16] 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
[17]
[18] and
COPS2 .
[19]
See also
References
^
a
b
c
GRCh38: Ensembl release 89: ENSG00000140968 –
Ensembl , May 2017
^
a
b
c
GRCm38: Ensembl release 89: ENSMUSG00000041515 –
Ensembl , May 2017
^
"Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^
"Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^
a
b
"Entrez Gene: IRF8 interferon regulatory factor 8" .
^ Weisz A, Marx P, Sharf R, Appella E, Driggers PH, Ozato K, Levi BZ (December 1992).
"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.
doi :
10.1016/S0021-9258(19)74081-2 .
PMID
1460054 . [
permanent dead link ]
^ Nehyba J, Hrdlicková R, Burnside J, Bose HR (June 2002).
"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.
doi :
10.1128/MCB.22.11.3942-3957.2002 .
PMC
133824 .
PMID
11997525 .
^ Tamura T, Ozato K (January 2002).
"ICSBP/IRF-8: its regulatory roles in the development of myeloid cells" . J. Interferon Cytokine Res . 22 (1): 145–52.
doi :
10.1089/107999002753452755 .
PMID
11846985 .
^ Yang J, Hu X, Zimmerman M, Torres CM, Yang D, Smith SB, Liu K (November 2011).
"Cutting edge: IRF8 regulates Bax transcription in vivo in primary myeloid cells" . J. Immunol . 187 (9): 4426–30.
doi :
10.4049/jimmunol.1101034 .
PMC
3197864 .
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 (April 2011).
"IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia" . Cancer Res . 71 (8): 2882–91.
doi :
10.1158/0008-5472.CAN-10-2493 .
PMC
3078194 .
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 (October 1996).
"Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene" . Cell . 87 (2): 307–17.
doi :
10.1016/S0092-8674(00)81348-3 .
PMID
8861914 .
S2CID
18065448 .
^ 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 (February 2009).
"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.
doi :
10.1158/0008-5472.CAN-08-2520 .
PMC
2633427 .
PMID
19155307 .
^ Yang D, Thangaraju M, Browning DD, Dong Z, Korchin B, Lev DC, Ganapathy V, Liu K (October 2007).
"IFN regulatory factor 8 mediates apoptosis in nonhemopoietic tumor cells via regulation of Fas expression" . J. Immunol . 179 (7): 4775–82.
doi :
10.4049/jimmunol.179.7.4775 .
PMID
17878376 .
^
a
b Yang D, Thangaraju M, Greeneltch K, Browning DD, Schoenlein PV, Tamura T, Ozato K, Ganapathy V, Abrams SI, Liu K (April 2007). "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.
doi :
10.1158/0008-5472.CAN-06-4068 .
PMID
17409439 .
^
"Tumorscape" . The Broad Institute. Archived from
the original on 2012-04-14. Retrieved 2012-07-05 .
^ McGough JM, Yang D, Huang S, Georgi D, Hewitt SM, Röcken C, Tänzer M, Ebert MP, Liu K (December 2008).
"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.
doi :
10.1158/1541-7786.MCR-08-0280 .
PMC
2605678 .
PMID
19074829 .
^ Schaper F, Kirchhoff S, Posern G, Köster M, Oumard A, Sharf R, Levi BZ, Hauser H (October 1998).
"Functional domains of interferon regulatory factor I (IRF-1)" . Biochem. J . 335 (1): 147–57.
doi :
10.1042/bj3350147 .
PMC
1219763 .
PMID
9742224 .
^ Sharf R, Azriel A, Lejbkowicz F, Winograd SS, Ehrlich R, Levi BZ (June 1995).
"Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors" . J. Biol. Chem . 270 (22): 13063–9.
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 (December 2000).
"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.
doi :
10.1074/jbc.M004900200 .
PMID
10991940 .
Illustrations
Further reading
Weisz A, Marx P, Sharf R, Appella E, Driggers PH, Ozato K, Levi BZ (1993).
"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.
doi :
10.1016/S0021-9258(19)74081-2 .
PMID
1460054 .
Sharf R, Azriel A, Lejbkowicz F, Winograd SS, Ehrlich R, Levi BZ (1995).
"Functional domain analysis of interferon consensus sequence binding protein (ICSBP) and its association with interferon regulatory factors" . J. Biol. Chem . 270 (22): 13063–9.
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 (1996).
"Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene" . Cell . 87 (2): 307–17.
doi :
10.1016/S0092-8674(00)81348-3 .
PMID
8861914 .
S2CID
18065448 .
Schaper F, Kirchhoff S, Posern G, Köster M, Oumard A, Sharf R, Levi BZ, Hauser H (1998).
"Functional domains of interferon regulatory factor I (IRF-1)" . Biochem. J . 335 (1): 147–57.
doi :
10.1042/bj3350147 .
PMC
1219763 .
PMID
9742224 .
Li W, Nagineni CN, Ge H, Efiok B, Chepelinsky AB, Egwuagu CE (1999).
"Interferon consensus sequence-binding protein is constitutively expressed and differentially regulated in the ocular lens" . J. Biol. Chem . 274 (14): 9686–91.
doi :
10.1074/jbc.274.14.9686 .
PMID
10092656 .
Li W, Nagineni CN, Hooks JJ, Chepelinsky AB, Egwuagu CE (1999). "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.
PMID
10102295 .
Rehli M, Poltorak A, Schwarzfischer L, Krause SW, Andreesen R, Beutler B (2000).
"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.
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 (2001).
"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.
doi :
10.1074/jbc.M004900200 .
PMID
10991940 .
Nehyba J, Hrdlicková R, Burnside J, Bose HR (2002).
"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.
doi :
10.1128/MCB.22.11.3942-3957.2002 .
PMC
133824 .
PMID
11997525 .
Zhu C, Saberwal G, Lu Y, Platanias LC, Eklund EA (2005).
"The interferon consensus sequence-binding protein activates transcription of the gene encoding neurofibromin 1" . J. Biol. Chem . 279 (49): 50874–85.
doi :
10.1074/jbc.M405736200 .
PMID
15371411 .
Liu J, Guan X, Tamura T, Ozato K, Ma X (2005).
"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.
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 (2005). "High-throughput mapping of a dynamic signaling network in mammalian cells". Science . 307 (5715): 1621–5.
Bibcode :
2005Sci...307.1621B .
doi :
10.1126/science.1105776 .
PMID
15761153 .
S2CID
39457788 .
Xiong H, Li H, Kong HJ, Chen Y, Zhao J, Xiong S, Huang B, Gu H, Mayer L, Ozato K, Unkeless JC (2005).
"Ubiquitin-dependent degradation of interferon regulatory factor-8 mediated by Cbl down-regulates interleukin-12 expression" . J. Biol. Chem . 280 (25): 23531–9.
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 (2006).
"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.
doi :
10.1074/jbc.M507788200 .
PMID
16484229 .
Huang W, Saberwal G, Horvath E, Zhu C, Lindsey S, Eklund EA (2006).
"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.
doi :
10.1128/MCB.00036-06 .
PMC
1592828 .
PMID
16914719 .
Dimberg A, Kårehed K, Nilsson K, Oberg F (2006). "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.
doi :
10.1111/j.1365-3083.2006.01827.x .
PMID
16918696 .
S2CID
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 (2013).
"Coronary Heart Disease in Systemic Lupus Erythematosus Is Associated with Interferon Regulatory Factor 8 Gene Variants" . Circ. Cardiovasc. Genet . 6 (3): 255–63.
doi :
10.1161/CIRCGENETICS.113.000044 .
PMID
23661672 .
Peng YB, Yerle M, Liu B (2007). "Mapping of nine porcine interferon regulatory factor genes". Anim. Genet . 37 (6): 600–1.
doi :
10.1111/j.1365-2052.2006.01525.x .
PMID
17121613 .
Huang W, Horvath E, Eklund EA (2007).
"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.
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 (2006).
"ICSBP/IRF-8 differentially regulates antigen uptake during dendritic-cell development and affects antigen presentation to CD4+ T cells" . Blood . 108 (2): 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 (2002).
"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.
doi :
10.1084/jem.20021263 .
PMC
2194263 .
PMID
12461077 .
External links
This article incorporates text from the
United States National Library of Medicine , which is in the
public domain .
(1) Basic domains
(1.1) Basic
leucine zipper (
bZIP )(1.2) Basic helix-loop-helix (
bHLH )
Group A Group B Group C bHLH-
PAS Group D Group E Group F bHLH-COE
(1.3)
bHLH-ZIP (1.4) NF-1 (1.5) RF-X (1.6) Basic helix-span-helix (bHSH)
(2)
Zinc finger DNA-binding domains
(2.1)
Nuclear receptor (Cys4 )
subfamily 1 subfamily 2 subfamily 3 subfamily 4 subfamily 5 subfamily 6 subfamily 0
(2.2) Other Cys4 (2.3) Cys2 His2 (2.4) Cys6 (2.5) Alternating composition (2.6) WRKY
(4) β-Scaffold factors with minor groove contacts
(0) Other transcription factors