Interferon regulatory factors (IRF) are proteins which regulate

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

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 the ...

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 wide ...

). 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 as ...

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 ba ...

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 limite ...

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 t ...

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 of ...

(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 recognize s ...

(TLR) and cytosolic PRRs, in the host cell. The downstream signaling pathways from PRR activation

phosphorylate In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

ubiquitously expressed IRFs (

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 ...

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 Interferon regulatory factor 7, also known as IRF7, is a member of the interferon regulatory factor family of transcription factors. Function IRF7 encodes interferon regulatory factor 7, a member of the interferon regulatory transcription fact ...

) 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 (TANK-binding kinase 1) is an enzyme with kinase activity. Specifically, it is a serine / threonine protein kinase. It is encoded by the TBK1 gene in humans. This kinase is mainly known for its role in innate immunity antiviral response. Howev ...

(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 Interferon regulatory factor 5 is a protein that in humans is encoded by the ''IRF5'' gene. The IRF family is a group of transcription factors that are involved in signaling for virus responses in mammals along with regulation of certain cellular ...

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 inhib ...

and

IRF4 Interferon regulatory factor 4 (IRF4) also known as ''MUM1'' is a protein that in humans is encoded by the ''IRF4'' gene, located at 6p25-p23. IRF4 functions as a key regulatory transcription factor in the development of human immune cells.Nam S, ...

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 the ...

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 l ...

) 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,

natural killer Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...

(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 + DCs, whereas IRF8 is essential for

CD8α CD8a (Cluster of Differentiation 8a), is a human gene. Function The CD8 antigen is a cell surface glycoprotein found on most cytotoxic T lymphocytes that mediates efficient cell-cell interactions within the immune system. The CD8 antigen, acti ...

+ 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 cel ...

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 granulocy ...

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 inf ...

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 progenitor Lymphopoiesis (lĭm'fō-poi-ē'sĭs) (or lymphocytopoiesis) is the generation of lymphocytes, which are one of the five types of white blood cells (WBCs). It is more formally known as lymphoid hematopoiesis. Disruption in lymphopoiesis can lead t ...

s (CLPs) to B-cell lineage. IRF8 and IRF4 are also required in the regulation of

germinal center Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, prolifera ...

(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. Comm ...

(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 abno ...

. 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,

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 ap ...

, cardiac hypertrophy,

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 atheroma, atheromatous plaque. At onset there are usu ...

, and

stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

Genes

IRF6 Interferon regulatory factor 6 also known as IRF6 is a protein that in humans is encoded by the ''IRF6'' gene. Function This gene encodes a member of the interferon regulatory transcription factor (IRF) family. Family members share a highly c ...

IRF9 Interferon regulatory factor 9 is a protein that in humans is encoded by the ''IRF9'' gene, previously known as ISGF3G. Interactions IRF9 has been shown to interact with STAT2 and STAT1 Signal transducer and activator of transcription 1 (STAT ...

References

External links