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FLASH GENE

Symbol

IRF8

contributors: mct/npt/pgu - updated : 11-06-2016

HGNC name	interferon regulatory factor 8
HGNC id	5358

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	16q24.1      Physical location : 85.932.773 - 85.956.209
Synonym name	interferon consensus sequence-binding protein
Synonym symbol(s)	ICSBP, IRF-8, ICSBP1, H-ICSBP

DNA

TYPE	functioning gene
STRUCTURE	23.44 kb     9 Exon(s)

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002163 9 - 2678 NP_002154 - 426 - 1995 7768900

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Lymphoid/Immune lymph node       highly   spleen       lowly   thymus       moderately

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune lymphocyte

cell lineage
cell lines
fluid/secretion	blood

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a conserved DNA-binding domain in the N-terminal region, (AAs 1-121) when fused in frame to the transcriptional activation domain of the herpes simplex VP16 (ICSBP-VP16) is a very strong activator of ICS-containing promoters
	a third functional domain that enables the association with IRFs
	a divergent C-terminal region that serves as the regulatory domain

HOMOLOGY

interspecies

ortholog to murine Icsbp1

Homologene

FAMILY

interferon (IFN) regulatory factor (IRF) family

CATEGORY

regulatory , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,nucleus

basic FUNCTION	regulating expression of genes stimulated by type I IFNs, namely IFN-alpha and IFN-beta
	also controling expression of IFN-alpha and IFN-beta-regulated genes that are induced by viral infection
	acts as a repressor of interferon consensus sequence (ICS) containing promoters that can be alleviated by interferons
	playing a negative regulatory role in cells of the immune system
	with IRF4 are dichotomous regulators of transcription in macrophages
	playing a role in regulating the proliferation and differentiation of hematopoietic progenitor cells
	IRF8-induced PTPN13 repression occurred in granulocyte/monocyte progenitor cells, and this activity increased during myeloid differentiation
	interferon regulatory transcription factor with leukemia-suppressor activity
	regulates genes that are involved in phagocyte function, proliferation, and apoptosis
	transcription factor expressed in immune cells, and a key regulatory molecule for osteoclastogenesis
	inhibits osteoclast formation under physiological and pathological conditions, suggesting a model where downregulation of inhibitory factors such as IRF8 contributes to TNFSF11-mediated osteoclastogenesis
	contributing to B cell development from hematopoietic stem cells in the bone marrow and implicated in the hierarchical regulatory network governing specification and commitment to the B cell fate
	functions in the GC B-cell transcription program and directly stimulates expression of the BCL6 gene
	key transcription factor for myeloid cell differentiation
	regulates ASAH1 expression to mediate apoptosis and suppresses myelogeneous leukemia
	interferon regulatory transcription factor with leukemia suppressor activity
	activates some target genes in myeloid progenitor cells and other target genes in mature phagocytes
	IRF8, ETV6 and HDAC3 cooperated to increase sensitivity to FAS-induced apoptosis
	during normal myelopoiesis, is involved in activation of phagocyte-specific genes, proliferation arrest, and increased sensitivity to FAS-induced apoptosis
	IRF5 and IRF8, two transcription factors with opposing functions, control TLR9 signaling in human plasmacytoid dendritic cells (pDCs)

CELLULAR PROCESS

nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

immunity/defense

text	immune response

PATHWAY

metabolism

signaling

a component

complex comprising BCOR-BCL6-IRF8 modulates BCL6-associated transcriptional regulation of germinal center B cell function

INTERACTION

DNA	binding to the IFN-stimulated response element (ISRE)

RNA

small molecule

protein	TRIP15
	FANCF is an IRF8 target gene
	PTPN13 is an IRF8 target gene (interacted with a cis element in the proximal PTPN13 promoter and repressed transcription)
	collaboration between IRF8 deficiency and MEIS1/MEIS3 in the acceleration of chronic myeloid leukemia-like disease
	requirement for IRF3, a master regulator of IFNB1 production, as a previously un-indentified interaction partner of IRF8
	IRF8 is critical for CST3 expression in primary dendritic cells
	ASAH1 is a general transcription target of IRF8 (directly binds to the ASAH1 promoter)
	PTPN13 is an IRF8 target (repression of PTPN13 by IRF8 requires cooperation with ETV6 and histone deacetylase 3)
	ETV6 interacts with IRF proteins, including IRF8, and represses transcription of various target genes during normal myelopoiesis
	ETV6-PDGFRB antagonizes the effects of ETV6 and IRF8 on PTPN13 transcription
	IRF8 inhibits TLR9-dependent gene expression by directly blocking the activity of IRF5
	more IRF8 bound to the IFN-stimulated response element of the IFIT1 gene than to those of the IFIT2 and the IFIT3 genes
	IRF8 is required for optimal activation of the NLRC4 inflammasome in bone-marrow-derived macrophages infected with Salmonella Typhimurium
	vitamin D regulation of ZMIZ1 and IRF8 in dendritic cells (DCs) and monocytes contribute to latitude-dependent autoimmune disease risk

cell & other

REGULATION

induced by

interferon gamma

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   in AML and chronic myeloid leukemia during blast crisis (CML-BC), and its deficiency may be functionally important for accumulation of chromosomal abnormalities during disease progression in these myeloid malignancies tumoral     --over   IRF8 and TNFSF13 expression was significantly higher in lymphomas with IGH rearrangements targeting these loci

Susceptibility

to systemic lupus erythematosus

Variant & Polymorphism SNP	rs11648084 and rs11644034 associated to systemic lupus erythematosus

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed immunology autoimmune Lupus IRF8 may provide important targets for therapeutic intervention in human lupus

ANIMAL & CELL MODELS

	Irf8-deficient mice exhibit uncontrolled clonal expansion of undifferentiated myeloid cells that can progress to a fatal blast crisis, thereby resembling human chronic myelogeneous leukemia (CML)