IRF8

IRF8

Interferon regulatory factor 8
Identifiers
Symbols  ; H-ICSBP; ICSBP; ICSBP1; IRF-8
External IDs GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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.

Contents

  • Function 1
  • Knockout studies 2
  • Clinical significance 3
  • See also 4
  • Interactions 5
  • References 6
  • Illustrations 7
  • Further reading 8
  • External links 9

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 CD11clowB220+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 linage-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.

See also

Interactions

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

References

  1. ^ a b "Entrez Gene: IRF8 interferon regulatory factor 8". 
  2. ^ 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.  
  3. ^ 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.  
  4. ^ 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.  
  5. ^ 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.  
  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 (April 2011). "IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia". Cancer Res. 71 (8): 2882–91.  
  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 (October 1996). "Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene". Cell 87 (2): 307–17.  
  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 (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.  
  9. ^ 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.  
  10. ^ 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.  
  11. ^ "Tumorscape". The Broad Institute. 
  12. ^ 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.  
  13. ^ 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.  
  14. ^ 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.  
  15. ^ 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.  

Illustrations

Further reading

  • Weisz A, Marx P, Sharf R, et al. (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.  
  • Sharf R, Azriel A, Lejbkowicz F, et al. (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.  
  • Holtschke T, Löhler J, Kanno Y, et al. (1996). "Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene.". Cell 87 (2): 307–17.  
  • Schaper F, Kirchhoff S, Posern G, et al. (1998). "Functional domains of interferon regulatory factor I (IRF-1).". Biochem. J. 335 (1): 147–57.  
  • Li W, Nagineni CN, Ge H, et al. (1999). "Interferon consensus sequence-binding protein is constitutively expressed and differentially regulated in the ocular lens.". J. Biol. Chem. 274 (14): 9686–91.  
  • Li W, Nagineni CN, Hooks JJ, et al. (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.  
  • Rehli M, Poltorak A, Schwarzfischer L, et al. (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.  
  • Cohen H, Azriel A, Cohen T, et al. (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.  
  • 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.  
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903.  
  • Zhu C, Saberwal G, Lu Y, et al. (2005). "The interferon consensus sequence-binding protein activates transcription of the gene encoding neurofibromin 1.". J. Biol. Chem. 279 (49): 50874–85.  
  • Liu J, Guan X, Tamura T, et al. (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.  
  • Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res. 14 (10B): 2121–7.  
  • Barrios-Rodiles M, Brown KR, Ozdamar B, et al. (2005). "High-throughput mapping of a dynamic signaling network in mammalian cells.". Science 307 (5715): 1621–5.  
  • Xiong H, Li H, Kong HJ, et al. (2005). "Ubiquitin-dependent degradation of interferon regulatory factor-8 mediated by Cbl down-regulates interleukin-12 expression.". J. Biol. Chem. 280 (25): 23531–9.  
  • Zhao J, Kong HJ, Li H, et al. (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.  
  • Huang W, Saberwal G, Horvath E, et al. (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.  
  • 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.  
  • 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. May 9. [Epub ahead of print] 6 (3): 255–63.  
  • Peng YB, Yerle M, Liu B (2007). "Mapping of nine porcine interferon regulatory factor genes.". Anim. Genet. 37 (6): 600–1.  
  • 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.  
  • Mattei Fabrizio, Schiavoni G, Borghi P, Venditti M, Canini I, Sestili P, Pietraforte I, Morse HC 3rd, 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.  
  • Schiavoni Giovanna, Mattei F, Sestili P, Borghi P, Venditti M, Morse HC 3rd, 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.  

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.