Protein-coding gene in the species Homo sapiens
Interferon regulatory factor 8 (IRF8) also known asinterferon consensus sequence-binding protein (ICSBP), is aprotein that in humans is encoded by theIRF8 gene .[ 5] [ 6] [ 7] transcription factor that plays critical roles in the regulation of lineage commitment and inmyeloid cell maturation including the decision for a common myeloid progenitor (CMP) todifferentiate into amonocyte precursor cell.
Interferon Consensus Sequence-binding protein (ICSBP) is atranscription factor of theinterferon regulatory factor (IRF ) family. Proteins of this family are composed of a conservedDNA-binding domain in theN-terminal region and a divergentC-terminal region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulatedresponse element (ISRE) and regulate expression of genes stimulated by type I IFNs, namelyIFN-α andIFN-β . IRF family proteins also control expression of IFN-α and IFN-β-regulated genes that are induced by viral infection.[ 5]
IFN-producing cells (mIPCs) were absent in all lymphoid organs from ICSBPknockout (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 moleculeICAM1 ,CD40 ,CD80 ,CD86 ) and of the T cell area-homing chemokine receptorCCR7 .[ 8]
Clinical significance [ edit ] In myeloid cells, IRF8 regulates the expression ofBax andFas to regulateapoptosis .[ 9] chronic myelogenous leukemia (CML), IRF8 regulates acidceramidase 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] 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 andSTAT1 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 atumor suppressor in humans.[ 15] colon carcinoma cells,[ 14] [ 16]
IRF8 has been shown tointeract withIRF1 [ 17] [ 18] COPS2 .[ 19]
^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. 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Chem .275 (50):39081– 9.doi :10.1074/jbc.M004900200 PMID 10991940 . 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). 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(1) Basic domains
(1.1) Basic leucine zipper (bZIP )(1.2) Basic helix-loop-helix (bHLH )
Group A Group B Group CPAS Group D Group E Group F
(1.3) bHLH-ZIP (1.4) NF-1 (1.5) RF-X (1.6) Basic helix-span-helix (bHSH)
(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
