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Interferon regulatory factors

Interferon regulatory factors (IRF) are proteins which regulate transcription of interferons (see regulation of gene expression).[1] 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.[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] The Kaposi 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 DNA methylation.[8]

Interferon regulatory factor transcription factor
interferon regulatory factor-2 dna binding domain, nmr, minimized average structure
Identifiers
SymbolIRF
PfamPF00605
InterProIPR001346
SCOP21if1 / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

Role in IFN signaling edit

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.[3] 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).[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 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.[3]

Role in immune cell development edit

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.[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 the differentiation of different subsets of DCs by stimulating subset-specific gene expression.[3] 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 edit

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).[10] Accumulating evidence also indicates that IRFs play a major role in the regulation of cellular responses linked to oncogenesis.[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 as hepatic steatosis, diabetes, cardiac hypertrophy, atherosclerosis, and stroke.[3]

Genes edit

See also edit

References edit

  1. ^ Paun A, Pitha PM (2007). "The IRF family, revisited". Biochimie. 89 (6–7): 744–53. doi:10.1016/j.biochi.2007.01.014. PMC 2139905. PMID 17399883.
  2. ^ a b Weisz A, Marx P, Sharf R, Appella E, Driggers PH, Ozato K, Levi BZ (December 1992). "Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon-inducible genes". The Journal of Biological Chemistry. 267 (35): 25589–96. doi:10.1016/S0021-9258(19)74081-2. PMID 1460054.
  3. ^ a b c d e f Zhao GN, Jiang DS, Li H (February 2015). "Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1852 (2): 365–78. doi:10.1016/j.bbadis.2014.04.030. PMID 24807060.
  4. ^ Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS (December 1994). "Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma". Science. 266 (5192): 1865–9. Bibcode:1994Sci...266.1865C. doi:10.1126/science.7997879. PMID 7997879. S2CID 29977325.
  5. ^ Offermann MK (2007). "Kaposi Sarcoma Herpesvirus-Encoded Interferon Regulator Factors". Kaposi Sarcoma Herpesvirus: New Perspectives. Current Topics in Microbiology and Immunology. Vol. 312. pp. 185–209. doi:10.1007/978-3-540-34344-8_7. ISBN 978-3-540-34343-1. PMID 17089798.
  6. ^ Moore PS, Boshoff C, Weiss RA, Chang Y (December 1996). "Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV". Science. 274 (5293): 1739–44. Bibcode:1996Sci...274.1739M. doi:10.1126/science.274.5293.1739. PMID 8939871. S2CID 29713179.
  7. ^ Gao SJ, Boshoff C, Jayachandra S, Weiss RA, Chang Y, Moore PS (October 1997). "KSHV ORF K9 (vIRF) is an oncogene which inhibits the interferon signaling pathway". Oncogene. 15 (16): 1979–85. doi:10.1038/sj.onc.1201571. PMID 9365244.
  8. ^ Rotondo JC, Borghi A, Selvatici R, Magri E, Bianchini E, Montinari E, et al. (August 2016). "Hypermethylation-Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus". JAMA Dermatology. 152 (8): 928–33. doi:10.1001/jamadermatol.2016.1336. PMID 27223861.
  9. ^ Shah, Masaud; Choi, Sangdun (2016), "Interferon Regulatory Factor", in Choi, Sangdun (ed.), Encyclopedia of Signaling Molecules, New York, NY: Springer, pp. 1–10, doi:10.1007/978-1-4614-6438-9_101496-1, ISBN 978-1-4614-6438-9
  10. ^ Santana-de Anda K, Gómez-Martín D, Díaz-Zamudio M, Alcocer-Varela J (December 2011). "Interferon regulatory factors: beyond the antiviral response and their link to the development of autoimmune pathology". Autoimmunity Reviews. 11 (2): 98–103. doi:10.1016/j.autrev.2011.08.006. PMID 21872684.
  11. ^ Yanai H, Negishi H, Taniguchi T (November 2012). "The IRF family of transcription factors: Inception, impact and implications in oncogenesis". Oncoimmunology. 1 (8): 1376–1386. doi:10.4161/onci.22475. PMC 3518510. PMID 23243601.

External links edit

  •   Media related to Interferon regulatory factors at Wikimedia Commons
  • Interferon+regulatory+factors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the public domain Pfam and InterPro: IPR001346

interferon, regulatory, factors, proteins, which, regulate, transcription, interferons, regulation, gene, expression, contain, conserved, terminal, region, about, amino, acids, which, folds, into, structure, that, binds, specifically, element, motifs, which, l. Interferon regulatory factors IRF are proteins which regulate transcription of interferons see regulation of gene expression 1 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 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 The Kaposi 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 DNA methylation 8 Interferon regulatory factor transcription factorinterferon regulatory factor 2 dna binding domain nmr minimized average structureIdentifiersSymbolIRFPfamPF00605InterProIPR001346SCOP21if1 SCOPe SUPFAMAvailable protein structures Pfam structures ECOD PDBRCSB PDB PDBe PDBjPDBsumstructure summary Contents 1 Role in IFN signaling 2 Role in immune cell development 3 Role in diseases 4 Genes 5 See also 6 References 7 External linksRole in IFN signaling editIRFs 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 3 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 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 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 3 Role in immune cell development editIn 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 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 the differentiation of different subsets of DCs by stimulating subset specific gene expression 3 For example IRF4 is required for the generation of CD4 DCs whereas IRF8 is essential for CD8a 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 editIRFs 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 10 Accumulating evidence also indicates that IRFs play a major role in the regulation of cellular responses linked to oncogenesis 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 as hepatic steatosis diabetes cardiac hypertrophy atherosclerosis and stroke 3 Genes editIRF1 IRF2 IRF3 IRF4 IRF5 IRF6 IRF7 IRF8 IRF9See also editInterferonReferences edit Paun A Pitha PM 2007 The IRF family revisited Biochimie 89 6 7 744 53 doi 10 1016 j biochi 2007 01 014 PMC 2139905 PMID 17399883 a b Weisz A Marx P Sharf R Appella E Driggers PH Ozato K Levi BZ December 1992 Human interferon consensus sequence binding protein is a negative regulator of enhancer elements common to interferon inducible genes The Journal of Biological Chemistry 267 35 25589 96 doi 10 1016 S0021 9258 19 74081 2 PMID 1460054 a b c d e f Zhao GN Jiang DS Li H February 2015 Interferon regulatory factors at the crossroads of immunity metabolism and disease Biochimica et Biophysica Acta BBA Molecular Basis of Disease 1852 2 365 78 doi 10 1016 j bbadis 2014 04 030 PMID 24807060 Chang Y Cesarman E Pessin MS Lee F Culpepper J Knowles DM Moore PS December 1994 Identification of herpesvirus like DNA sequences in AIDS associated Kaposi s sarcoma Science 266 5192 1865 9 Bibcode 1994Sci 266 1865C doi 10 1126 science 7997879 PMID 7997879 S2CID 29977325 Offermann MK 2007 Kaposi Sarcoma Herpesvirus Encoded Interferon Regulator Factors Kaposi Sarcoma Herpesvirus New Perspectives Current Topics in Microbiology and Immunology Vol 312 pp 185 209 doi 10 1007 978 3 540 34344 8 7 ISBN 978 3 540 34343 1 PMID 17089798 Moore PS Boshoff C Weiss RA Chang Y December 1996 Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV Science 274 5293 1739 44 Bibcode 1996Sci 274 1739M doi 10 1126 science 274 5293 1739 PMID 8939871 S2CID 29713179 Gao SJ Boshoff C Jayachandra S Weiss RA Chang Y Moore PS October 1997 KSHV ORF K9 vIRF is an oncogene which inhibits the interferon signaling pathway Oncogene 15 16 1979 85 doi 10 1038 sj onc 1201571 PMID 9365244 Rotondo JC Borghi A Selvatici R Magri E Bianchini E Montinari E et al August 2016 Hypermethylation Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus JAMA Dermatology 152 8 928 33 doi 10 1001 jamadermatol 2016 1336 PMID 27223861 Shah Masaud Choi Sangdun 2016 Interferon Regulatory Factor in Choi Sangdun ed Encyclopedia of Signaling Molecules New York NY Springer pp 1 10 doi 10 1007 978 1 4614 6438 9 101496 1 ISBN 978 1 4614 6438 9 Santana de Anda K Gomez Martin D Diaz Zamudio M Alcocer Varela J December 2011 Interferon regulatory factors beyond the antiviral response and their link to the development of autoimmune pathology Autoimmunity Reviews 11 2 98 103 doi 10 1016 j autrev 2011 08 006 PMID 21872684 Yanai H Negishi H Taniguchi T November 2012 The IRF family of transcription factors Inception impact and implications in oncogenesis Oncoimmunology 1 8 1376 1386 doi 10 4161 onci 22475 PMC 3518510 PMID 23243601 External links edit nbsp Media related to Interferon regulatory factors at Wikimedia Commons Interferon regulatory factors at the U S National Library of Medicine Medical Subject Headings MeSH This article incorporates text from the public domain Pfam and InterPro IPR001346 Retrieved from https en wikipedia org w index php title Interferon regulatory factors amp oldid 1187422580, wikipedia, wiki, book, books, library,

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