Interferon regulatory factor 8 (IRF8) also known as interferon consensus sequence-binding protein (ICSBP), is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the ''IRF8''

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. IRF8 is a

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

that plays critical roles in the regulation of lineage commitment and in myeloid

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

maturation including the decision for a common myeloid progenitor (CMP) to differentiate into a

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

precursor cell.

Function

Interferon Consensus Sequence-binding protein (ICSBP) is a

of the interferon regulatory factor ( IRF) family. Proteins of this family are composed of a conserved

DNA-binding domain A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a gener ...

in the N-terminal region and a divergent

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...

region that serves as the regulatory domain. The IRF family proteins bind to the IFN-stimulated

response element Response elements are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes. Under conditions of stress, a transcription activator protein binds ...

(ISRE) and regulate expression of genes stimulated by type I IFNs, namely

IFN-α The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyt ...

and

IFN-β The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyt ...

. IRF family proteins also control expression of IFN-α and IFN-β-regulated genes that are induced by viral infection.

Knockout studies

IFN-producing cells (mIPCs) were absent in all lymphoid organs from ICSBP knockout (KO) mice, as revealed by lack of CD11c^lowB220⁺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 ICAM-1 (Intercellular Adhesion Molecule 1) also known as CD54 (Cluster of Differentiation 54) is a protein that in humans is encoded by the ''ICAM1'' gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial ...

CD40 Cluster of differentiation 40, CD40 is a costimulatory protein found on antigen-presenting cells and is required for their activation. The binding of CD154 ( CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of d ...

CD80 The Cluster of differentiation 80 (also CD80 and B7-1) is a B7, type I membrane protein in the immunoglobulin superfamily, with an extracellular immunoglobulin constant-like domain and a variable-like domain required for receptor binding. It is cl ...

CD86 Cluster of Differentiation 86 (also known as CD86 and B7-2) is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells (including memory B-cells), and on other antigen-presenting cells. Along with CD80, CD8 ...

) and of the T cell area-homing chemokine receptor CCR7.

Clinical significance

In myeloid cells, IRF8 regulates the expression of Bax and Fas to regulate apoptosis. In chronic myelogenous leukemia (CML), IRF8 regulates acid

ceramidase Ceramidase (, ''acylsphingosine deacylase'', ''glycosphingolipid ceramide deacylase'') is an enzyme which cleaves fatty acids from ceramide, producing sphingosine (SPH) which in turn is phosphorylated by a sphingosine kinase to form sphingosine- ...

to mediate CML apoptosis. IRF8 is highly expressed in myeloid cells and was originally identified in as a critical lineage-specific transcription factor for myeloid cell differentiation, 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 Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the ''STAT1'' gene. It is a member of the STAT protein family. Function All STAT molecules are phosphorylated by receptor associ ...

to mediate apoptosis in non-hemotopoietic cancer cells. 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 A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...

in humans. Molecular analysis indicated that the IRF8 gene promoter is hypermethylated in human

colon carcinoma Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...

cells, 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 Interferon regulatory factor 1 is a protein that in humans is encoded by the ''IRF1'' gene. Function Interferon regulatory factor 1 was the first member of the interferon regulatory transcription factor (IRF) family identified. Initially descr ...

and

COPS2 COP9 signalosome complex subunit 2 is a protein that in humans is encoded by the ''COPS2'' gene. It encodes a subunit of the COP9 signalosome. Interactions COPS2 has been shown to interact with: * DAX1, * IRF8 Interferon regulatory factor 8 ...

References

Illustrations

External links

* {{DEFAULTSORT:Irf8 Transcription factors