Interferon regulatory factors: Difference between revisions
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'''Interferon regulatory factors''' ('''IRF''') are proteins which regulate [[Transcription (genetics)|transcription]] of [[interferon]]s (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 | doi = 10.1016/j.biochi.2007.01.014| pmc = 2139905 |
'''Interferon regulatory factors''' ('''IRF''') are proteins which regulate [[Transcription (genetics)|transcription]] of [[interferon]]s (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 | doi = 10.1016/j.biochi.2007.01.014| pmc = 2139905 }}</ref> Interferon regulatory factors contain a [[conserved sequence|conserved]] [[N-terminal]] region of about 120 [[amino acids]], which [[protein folding|fold]]s into a [[secondary structure|structure]] that binds specifically to the IRF-element (IRF-E) motifs, which is located [[upstream and downstream (DNA)|upstream]] of the interferon [[gene]]s.<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 = J. Biol. Chem. | volume = 267 | issue = 35 | pages = 25589–96 |date=December 1992 | pmid = 1460054 }}</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|last=Zhao|first=Guang-Nian|last2=Jiang|first2=Ding-Sheng|last3=Li|first3=Hongliang|date=2015-02|title=Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease|url=http://dx.doi.org/10.1016/j.bbadis.2014.04.030|journal=Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease|volume=1852|issue=2|pages=365–378|doi=10.1016/j.bbadis.2014.04.030|issn=0925-4439}}</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, [[Kaposi's sarcoma-associated 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| bibcode = 1994Sci...266.1865C | url = https://zenodo.org/record/842914}} </ref> is a cancer virus that encodes four different IRF-like genes;<ref name="pmid170897989">{{cite journal |vauthors=Offermann MK | title = Kaposi sarcoma herpesvirus-encoded interferon regulator factors | journal = Curr Top Microbiol Immunol | series = Current Topics in Microbiology and Immunology | volume = 312 | pages = 185–209 |date=2007 | pmid = 17089798 | doi = 10.1007/978-3-540-34344-8_7| isbn = 978-3-540-34343-1 }} </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| bibcode = 1996Sci...274.1739M | s2cid = 29713179 }}</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 [[DNA methylation|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 | 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=2016 | pmid = 27223861 | doi = 10.1001/jamadermatol.2016.1336 }}</ref> |
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== Role in IFN Signaling == |
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IRFs primarily regulate [[Interferon type I|type I IFN]]<nowiki/>s 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 receptor|Pattern Recognition Receptors]] (PRRs), including various types of [[Toll-like receptor|Toll-like Receptors]] (TLR) and cytosolic PRRs, in the host cell<ref name=":0" />. The downstream signaling pathways from PRR activation [[Phosphorylation|phosphorylate]] ubiquitously expressed IRFs ([[IRF1]], [[IRF3]], and [[IRF7]]) through IRF [[Kinase|kinases]], such as [[TANK-binding kinase 1]] (TBK1)<ref>{{Citation|last=Shah|first=Masaud|title=Interferon Regulatory Factor|date=2016|url=https://doi.org/10.1007/978-1-4614-6438-9_101496-1|work=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|access-date=2021-03-08|last2=Choi|first2=Sangdun}}</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 [[Inflammatory cytokine|pro-inflammatory cytokine]]<nowiki/>s. |
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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" />. |
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== Role in Immune Cell Development == |
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In addition to the signal transduction functions of IRFs in [[Innate immune system|innate immune responses]], multiple IRFs (IRF1, IRF2, IRF4, and [[IRF8]]) play essential roles in the development of immune cells, including [[Dendritic cell|dendritic]], [[Myeloid tissue|myeloid]], [[Natural killer cell|natural killer]] (NK), [[B cell|B]], and [[T cell|T]] cells<ref name=":0" />. |
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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 [[Cellular differentiation|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 [[CD8A|CD8α]] + DCs. In addition to IRF4 and IRF8, IRF1 and IRF2 are also involved in DC subset development. |
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IRF8 has also been implicated in the promotion of [[macrophage]] development from [[common myeloid progenitor]]<nowiki/>s (CMPs) and the inhibition of granulocytic differentiation during the divergence of [[Granulocyte|granulocytes]] and [[Monocyte|monocytes]]. |
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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|common lymphoid progenitors]] (CLPs) to B-cell lineage. IRF8 and IRF4 are also required in the regulation of [[germinal center]] (GC) B cell differentiation. |
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== Role in Diseases == |
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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]]<nowiki/>s that are linked to activation of IFN type I system, such as [[systemic lupus erythematosus]] (SLE)<ref>{{Cite journal|last=Santana-de Anda|first=Karina|last2=Gómez-Martín|first2=Diana|last3=Díaz-Zamudio|first3=Mariana|last4=Alcocer-Varela|first4=Jorge|date=2011-12|title=Interferon regulatory factors: Beyond the antiviral response and their link to the development of autoimmune pathology|url=http://dx.doi.org/10.1016/j.autrev.2011.08.006|journal=Autoimmunity Reviews|volume=11|issue=2|pages=98–103|doi=10.1016/j.autrev.2011.08.006|issn=1568-9972}}</ref>. Accumulating evidence also indicates that IRFs play a major role in the regulation of cellular responses linked to [[Carcinogenesis|oncogenesis]]<ref>{{Cite journal|last=Yanai|first=Hideyuki|last2=Negishi|first2=Hideo|last3=Taniguchi|first3=Tadatsugu|date=2012-11|title=The IRF family of transcription factors|url=http://dx.doi.org/10.4161/onci.22475|journal=OncoImmunology|volume=1|issue=8|pages=1376–1386|doi=10.4161/onci.22475|issn=2162-402X}}</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 [[Fatty liver disease|hepatic steatosis]], [[diabetes]], [[Ventricular hypertrophy|cardiac hypertrophy]], [[atherosclerosis]], and [[stroke]]<ref name=":0" />. |
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==Genes== |
==Genes== |
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Revision as of 18:28, 8 March 2021
| 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 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]
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[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
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
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
See also
References
- ^ 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". J. Biol. Chem. 267 (35): 25589–96. PMID 1460054.
- ^ a b c d e f Zhao, Guang-Nian; Jiang, Ding-Sheng; Li, Hongliang (2015-02). "Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1852 (2): 365–378. doi:10.1016/j.bbadis.2014.04.030. ISSN 0925-4439.
{{cite journal}}: Check date values in:|date=(help) - ^ 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.
- ^ Offermann MK (2007). "Kaposi sarcoma herpesvirus-encoded interferon regulator factors". Curr Top Microbiol Immunol. Current Topics in Microbiology and Immunology. 312: 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, Corazza M, Virgili A, Tognon M, Martini F (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), Choi, Sangdun (ed.), "Interferon Regulatory Factor", 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, retrieved 2021-03-08
- ^ Santana-de Anda, Karina; Gómez-Martín, Diana; Díaz-Zamudio, Mariana; Alcocer-Varela, Jorge (2011-12). "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. ISSN 1568-9972.
{{cite journal}}: Check date values in:|date=(help) - ^ Yanai, Hideyuki; Negishi, Hideo; Taniguchi, Tadatsugu (2012-11). "The IRF family of transcription factors". OncoImmunology. 1 (8): 1376–1386. doi:10.4161/onci.22475. ISSN 2162-402X.
{{cite journal}}: Check date values in:|date=(help)
External links
Media related to Interferon regulatory factors at Wikimedia Commons- Interferon+regulatory+factors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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