{{Short description|Protein family}} {{Infobox protein family | Symbol = IRF | Name = Interferon regulatory factor transcription factor | image = PDB 1irf EBI.jpg | width = | caption = interferon regulatory factor-2 dna binding domain, nmr, minimized average structure | Pfam = PF00605 | Pfam_clan = | InterPro = IPR001346 | SMART = | PROSITE = | MEROPS = | SCOP = 1if1 | TCDB = | OPM family = | OPM protein = | CAZy = | CDD = }} '''Interferon regulatory factors''' ('''IRF''') are proteins which regulate transcription of interferons (see regulation of gene expression).<ref name="pmid17399883">{{cite journal | vauthors = Paun A, Pitha PM | title = The IRF family, revisited | journal = Biochimie | volume = 89 | issue = 6–7 | pages = 744–53 | year = 2007 | pmid = 17399883 | pmc = 2139905 | doi = 10.1016/j.biochi.2007.01.014 }}</ref> Interferon regulatory factors contain a conserved N-terminal region of about 120 amino acids, which folds into a structure that binds specifically to the IRF-element (IRF-E) motifs, which is located upstream of the interferon genes.<ref name="pmid1460054">{{cite journal | vauthors = Weisz A, Marx P, Sharf R, Appella E, Driggers PH, Ozato K, Levi BZ | title = Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes | journal = The Journal of Biological Chemistry | volume = 267 | issue = 35 | pages = 25589–96 | date = December 1992 | doi = 10.1016/S0021-9258(19)74081-2 | pmid = 1460054 | doi-access = free }}</ref> Some viruses have evolved defense mechanisms that regulate and interfere with IRF functions to escape the host immune system.<ref name=":0">{{cite journal | vauthors = Zhao GN, Jiang DS, Li H | title = Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1852 | issue = 2 | pages = 365–78 | date = February 2015 | pmid = 24807060 | doi = 10.1016/j.bbadis.2014.04.030 | doi-access = free }}</ref> For instance, the remaining parts of the interferon regulatory factor sequence vary depending on the precise function of the protein.<ref name="pmid1460054"/> The Kaposi sarcoma herpesvirus, KSHV,<ref name="pmid7997879">{{cite journal | vauthors = Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS | title = Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma | journal = Science | volume = 266 | issue = 5192 | pages = 1865–9 | date = December 1994 | pmid = 7997879 | doi = 10.1126/science.7997879 | url = https://zenodo.org/record/842914 | bibcode = 1994Sci...266.1865C | s2cid = 29977325 }}</ref> is a cancer virus that encodes four different IRF-like genes;<ref name="pmid170897989">{{cite book | vauthors = Offermann MK | chapter = Kaposi Sarcoma Herpesvirus-Encoded Interferon Regulator Factors | title = Kaposi Sarcoma Herpesvirus: New Perspectives | volume = 312 | pages = 185–209 | date = 2007 | pmid = 17089798 | doi = 10.1007/978-3-540-34344-8_7 | isbn = 978-3-540-34343-1 | series = Current Topics in Microbiology and Immunology }}</ref> including vIRF1,<ref name="pmid8939871">{{cite journal | vauthors = Moore PS, Boshoff C, Weiss RA, Chang Y | title = Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV | journal = Science | volume = 274 | issue = 5293 | pages = 1739–44 | date = December 1996 | pmid = 8939871 | doi = 10.1126/science.274.5293.1739 | s2cid = 29713179 | bibcode = 1996Sci...274.1739M }}</ref> which is a transforming oncoprotein that inhibits type 1 interferon activity.<ref name="pmid9365244">{{cite journal | vauthors = Gao SJ, Boshoff C, Jayachandra S, Weiss RA, Chang Y, Moore PS | title = KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway | journal = Oncogene | volume = 15 | issue = 16 | pages = 1979–85 | date = October 1997 | pmid = 9365244 | doi = 10.1038/sj.onc.1201571 | doi-access = free }}</ref> In addition, the expression of IRF genes is under epigenetic regulation by promoter DNA methylation.<ref name="pmid27223861">{{cite journal | vauthors = Rotondo JC, Borghi A, Selvatici R, Magri E, Bianchini E, Montinari E, Corazza M, Virgili A, Tognon M, Martini F | display-authors = 6 | title = Hypermethylation-Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus | journal = JAMA Dermatology | volume = 152 | issue = 8 | pages = 928–33 | date = August 2016 | pmid = 27223861 | doi = 10.1001/jamadermatol.2016.1336 }}</ref>
== 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 (PRRs), including various types of Toll-like Receptors (TLR) and cytosolic PRRs, in the host cell.<ref name=":0" /> The downstream signaling pathways from PRR activation phosphorylate ubiquitously expressed IRFs (IRF1, IRF3, and IRF7) through IRF kinases, such as TANK-binding kinase 1 (TBK1).<ref>{{Citation|last1=Shah|first1=Masaud|title=Interferon Regulatory Factor|date=2016|encyclopedia=Encyclopedia of Signaling Molecules|pages=1–10|editor-last=Choi|editor-first=Sangdun|place=New York, NY|publisher=Springer|language=en|doi=10.1007/978-1-4614-6438-9_101496-1|isbn=978-1-4614-6438-9|last2=Choi|first2=Sangdun|doi-access=free}}</ref> 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 and IRF4 regulate the activation of IFNs and pro-inflammatory cytokines through inhibition. IRF2 contains a repressor region that downregulates expression of type I IFNs. IRF4 competes with IRF5, and inhibits its sustained activity.<ref name=":0" />
== 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) play essential roles in the development of immune cells, including dendritic, myeloid, natural killer (NK), B, and T cells.<ref name=":0" />
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.<ref name=":0" /> For example, IRF4 is required for the generation of CD4 + 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 development from common myeloid progenitors (CMPs) and the inhibition of granulocytic differentiation during the divergence of granulocytes and monocytes.
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 diseases that are linked to activation of IFN type I system, such as systemic lupus erythematosus (SLE).<ref>{{cite journal | vauthors = Santana-de Anda K, Gómez-Martín D, Díaz-Zamudio M, Alcocer-Varela J | title = Interferon regulatory factors: beyond the antiviral response and their link to the development of autoimmune pathology | journal = Autoimmunity Reviews | volume = 11 | issue = 2 | pages = 98–103 | date = December 2011 | pmid = 21872684 | doi = 10.1016/j.autrev.2011.08.006 | url = http://dx.doi.org/10.1016/j.autrev.2011.08.006 | url-access = subscription }}</ref> Accumulating evidence also indicates that IRFs play a major role in the regulation of cellular responses linked to oncogenesis.<ref>{{cite journal | vauthors = Yanai H, Negishi H, Taniguchi T | title = The IRF family of transcription factors: Inception, impact and implications in oncogenesis | journal = Oncoimmunology | volume = 1 | issue = 8 | pages = 1376–1386 | date = November 2012 | pmid = 23243601 | doi = 10.4161/onci.22475|pmc=3518510 | doi-access = free }}</ref> 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, cardiac hypertrophy, atherosclerosis, and stroke.<ref name=":0" />
==Genes== * IRF1 * IRF2 * IRF3 * IRF4 * IRF5 * IRF6 * IRF7 * IRF8 * IRF9
== See also == * Interferon
== References == {{Reflist}}
== External links == * {{Commons category-inline}} * {{MeshName|Interferon+regulatory+factors}}
{{JAK-STAT signaling pathway}} {{Transcription factors|g3}} {{InterPro content|IPR001346}}
Category:Transcription factors Category:Protein families