Interferon regulatory factors (IRF) are proteins which regulate transcription of

interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten th ...

s (see

regulation of gene expression Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are w ...

). Interferon regulatory factors contain a conserved

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...

region of about 120

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

, which folds into a

structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such a ...

that binds specifically to the IRF-element (IRF-E) motifs, which is located

upstream Upstream may refer to: * Upstream (bioprocess) * ''Upstream'' (film), a 1927 film by John Ford * Upstream (networking) * ''Upstream'' (newspaper), a newspaper covering the oil and gas industry * Upstream (petroleum industry) * Upstream (software ...

of the interferon

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 ...

s. Some viruses have evolved defense mechanisms that regulate and interfere with IRF functions to escape the host immune system. For instance, the remaining parts of the interferon regulatory factor sequence vary depending on the precise function of the protein. The

Kaposi sarcoma Kaposi's sarcoma (KS) is a type of cancer that can form masses in the skin, in lymph nodes, in the mouth, or in other organs. The skin lesions are usually painless, purple and may be flat or raised. Lesions can occur singly, multiply in a limit ...

herpesvirus, KSHV, is a cancer virus that encodes four different IRF-like genes; including vIRF1, which is a transforming oncoprotein that inhibits type 1 interferon activity. In addition, the expression of IRF genes is under epigenetic regulation by promoter DNA

methylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...

Role in IFN Signaling

IRFs primarily regulate type I IFNs in the host after pathogen invasion and are considered the crucial mediators of an antiviral response. Following a viral infection, pathogens are detected by

Pattern Recognition Receptors Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells o ...

(PRRs), including various types of

Toll-like Receptors Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recogniz ...

(TLR) and cytosolic PRRs, in the host cell. The downstream signaling pathways from PRR activation phosphorylate ubiquitously expressed IRFs ( IRF1,

IRF3 Interferon regulatory factor 3, also known as IRF3, is an interferon regulatory factor. Function IRF3 is a member of the interferon regulatory transcription factor (IRF) family. IRF3 was originally discovered as a homolog of IRF1 and IRF2. ...

, and IRF7) through IRF

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

s, such as TANK-binding kinase 1 (TBK1). Phosphorylated IRFs are translocated to the nucleus where they bind to IRF-E motifs and activate the transcription of Type I IFNs. In addition to IFNs, IRF1 and IRF5 has been found to induce transcription of pro-inflammatory cytokines. Some IFNs like

IRF2 Interferon regulatory factor 2 is a protein that in humans is encoded by the ''IRF2'' gene. Function IRF2 encodes interferon regulatory factor 2, a member of the interferon regulatory transcription factor (IRF) family. IRF2 competitively inhi ...

and IRF4 regulate the activation of IFNs and pro-inflammatory cytokines through inhibition. IRF2 contains a

repressor In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to t ...

region that downregulates expression of type I IFNs. IRF4 competes with IRF5, and inhibits its sustained activity.

Role in Immune Cell Development

In addition to the signal transduction functions of IRFs in innate immune responses, multiple IRFs (IRF1, IRF2, IRF4, and

IRF8 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. IRF8 is a transcription factor that plays critical roles in the regulation of ...

) play essential roles in the development of immune cells, including

dendritic Dendrite derives from the Greek word "dendron" meaning ( "tree-like"), and may refer to: Biology *Dendrite, a branched projection of a neuron * Dendrite (non-neuronal), branching projections of certain skin cells and immune cells Physical *Dendr ...

myeloid Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + '' -oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue o ...

, natural killer (NK), B, and T cells. Dendritic cells (DC) are a group of heterogeneous cells that can be divided into different subsets with distinct functions and developmental programs. IRF4 and IRF8 specify and direct the differentiation of different subsets of DCs by stimulating subset-specific gene expression. For example, IRF4 is required for the generation of

CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic ce ...

+ DCs, whereas IRF8 is essential for CD8α + DCs. In addition to IRF4 and IRF8, IRF1 and IRF2 are also involved in DC subset development. IRF8 has also been implicated in the promotion of

macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

development from

common myeloid progenitor CFU-GEMM is a colony forming unit that generates myeloid cells. CFU-GEMM cells are the oligopotential progenitor cells for myeloid cells; they are thus also called common myeloid progenitor cells or myeloid stem cells. "GEMM" stands for granulocyt ...

s (CMPs) and the inhibition of granulocytic differentiation during the divergence of

granulocyte Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They ha ...

s and

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 ...

s. IRF8 and IRF4 are also involved in the regulation of B and T-cell development at multiple stages. IRF8 and IRF4 function redundantly to drive common lymphoid progenitors (CLPs) to B-cell lineage. IRF8 and IRF4 are also required in the regulation of germinal center (GC) B cell differentiation.

Role in Diseases

IRFs are critical regulators of immune responses and immune cell development, and abnormalities in IRF expression and function have been linked to numerous diseases. Due to their critical role in IFN type I activation, IRFs are implicated in

autoimmune disease An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...

s that are linked to activation of IFN type I system, such as

systemic lupus erythematosus Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Commo ...

(SLE). Accumulating evidence also indicates that IRFs play a major role in the regulation of cellular responses linked to

oncogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...

. In addition to autoimmune diseases and cancers, IRFs are also found to be involved in the pathogenesis of metabolic, cardiovascular, and neurological diseases, such as

hepatic steatosis Fatty liver disease (FLD), also known as hepatic steatosis, is a condition where excess fat builds up in the liver. Often there are no or few symptoms. Occasionally there may be tiredness or pain in the upper right side of the abdomen. Complica ...

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

cardiac hypertrophy Ventricular hypertrophy (VH) is thickening of the walls of a ventricle (lower chamber) of the heart. Although left ventricular hypertrophy (LVH) is more common, right ventricular hypertrophy (RVH), as well as concurrent hypertrophy of both ventri ...

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...

, and

stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...

Genes

* IRF1 *

* IRF4 * IRF5 * IRF6 * IRF7 *

* IRF9

References

External links