| Interferon regulatory factor transcription factor | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 interferon regulatory factor-2 dna binding domain, nmr, minimized average structure | |||||||||
| Identifiers | |||||||||
| Symbol | IRF | ||||||||
| Pfam | PF00605 | ||||||||
| InterPro | IPR001346 | ||||||||
| SCOP2 | 1if1 /SCOPe /SUPFAM | ||||||||
| |||||||||
Interferon regulatory factors (IRF) are proteins which regulatetranscription ofinterferons (seeregulation of gene expression).[1] Interferon regulatory factors contain aconservedN-terminal region of about 120amino acids, whichfolds into astructure that binds specifically to the IRF-element (IRF-E) motifs, which is locatedupstream of the interferongenes.[2] Some viruses have evolved defense mechanisms that regulate and interfere with IRF functions to escape the host immune system.[3] For instance, the remaining parts of the interferon regulatory factor sequence vary depending on the precise function of the protein.[2] TheKaposi sarcoma herpesvirus,KSHV,[4] is a cancer virus that encodes four different IRF-like genes;[5] including vIRF1,[6] which is a transforming oncoprotein that inhibits type 1 interferon activity.[7] In addition, the expression of IRF genes is under epigenetic regulation by promoter DNAmethylation.[8]
IRFs primarily regulatetype 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 byPattern Recognition Receptors (PRRs), including various types ofToll-like Receptors (TLR) and cytosolic PRRs, in the host cell.[3] The downstream signaling pathways from PRR activationphosphorylate ubiquitously expressed IRFs (IRF1,IRF3, andIRF7) through IRFkinases, such asTANK-binding kinase 1 (TBK1).[9] 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 andIRF5 has been found to induce transcription ofpro-inflammatory cytokines.
Some IFNs likeIRF2 andIRF4 regulate the activation of IFNs and pro-inflammatory cytokines through inhibition. IRF2 contains arepressor region that downregulates expression of type I IFNs. IRF4 competes with IRF5, and inhibits its sustained activity.[3]
In addition to the signal transduction functions of IRFs ininnate immune responses, multiple IRFs (IRF1, IRF2, IRF4, andIRF8) play essential roles in the development of immune cells, includingdendritic,myeloid,natural killer (NK),B, andT cells.[3]
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 thedifferentiation of different subsets of DCs by stimulating subset-specific gene expression.[3] For example, IRF4 is required for the generation ofCD4 + DCs, whereas IRF8 is essential forCD8α + 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 ofmacrophage development fromcommon myeloid progenitors (CMPs) and the inhibition of granulocytic differentiation during the divergence ofgranulocytes andmonocytes.
IRF8 and IRF4 are also involved in the regulation of B and T-cell development at multiple stages. IRF8 and IRF4 function redundantly to drivecommon lymphoid progenitors (CLPs) to B-cell lineage. IRF8 and IRF4 are also required in the regulation ofgerminal center (GC) B cell differentiation.
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 inautoimmune diseases that are linked to activation of IFN type I system, such assystemic lupus erythematosus (SLE).[10] Accumulating evidence also indicates that IRFs play a major role in the regulation of cellular responses linked tooncogenesis.[11] In addition to autoimmune diseases and cancers, IRFs are also found to be involved in the pathogenesis of metabolic, cardiovascular, and neurological diseases, such ashepatic steatosis,diabetes,cardiac hypertrophy,atherosclerosis, andstroke.[3]
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