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 | |||||||||
| Symbol | IRF | ||||||||
| Pfam | PF00605 | ||||||||
| InterPro | IPR001346 | ||||||||
| SCOP2 | 1if1 / SCOPe / SUPFAM | ||||||||
| |||||||||
Role 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 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
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
editSee also
editReferences
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, 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.
- ^ 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)
