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HGNC Approved Gene Symbol: IRF7
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:612,555-615,950 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.5 | ?Immunodeficiency 39 | 616345 | Autosomal recessive | 3 |
The expression of interferon genes (e.g., IFNB, 147640) in response to viral infection (e.g., Epstein-Barr virus, EBV) or cytokines is regulated at the transcriptional level by interferon regulatory factors (IRFs).
Using a yeast 1-hybrid system with an EBV protein-binding sequence as bait, Zhang and Pagano (1997) obtained 2 cDNAs encoding variants of IRF7. Sequence analysis showed that the cDNAs encode identical proteins except that IRF7B lacks 29 amino acids that are present in the putative 503-amino acid IRF7A protein. The highest sequence identity with other IRF family members is in the conserved N-terminal DNA-binding domain. By EST database searching, Zhang and Pagano (1997) identified another truncated splice variant, IRF7C, which encodes a 164-amino acid protein. Northern blot analysis revealed expression of 2 major IRF7 transcripts of 2.0 and 2.6 kb predominantly in spleen, thymus, and peripheral blood leukocytes (PBLs). The smaller transcript is only weakly expressed in PBLs. Western blot analysis demonstrated that the IRF7A, B, and C isoforms are expressed as 69-, 67-, and 23-kD proteins. Expression of IRF7A but not IRF7B or C was detected in normal PBLs. Electrophoretic mobility shift analysis confirmed that the IRF7 N-terminal DNA-binding domain interacts with the interferon-stimulated response element (ISRE; see ISGF3G, 147574) in IFN promoters and also to an ISRE in the Q promoter (Qp) of EBV nuclear antigen-1 (EBNA1). Western blot analysis detected high levels of IRF7 in type III (positive for multiple EBV antigens) EBV latently infected cells but not in type I (positive for EBNA1 antigen only) latently infected cells, corresponding inversely with endogenous Qp activity. Zhang and Pagano (1997) proposed that IRF7 is a repressor of Qp in type III latency.
Au et al. (1998) identified an IRF7 isoform, which they designated IRF7H, that encodes a deduced 514-amino acid protein with highest homology to IRF3 (603734). Unlike IRF3, expression of this isoform is restricted to lymphoid cells. Northern blot analysis showed that IRF7 is inducible by lipopolysaccharide, virus infection, and IFNA (147660) but not by IFNG (147570). Functional analysis revealed a transactivation domain located C terminal to the DNA-binding domain. Newcastle disease virus infection facilitates transfer of overexpressed IRF7H from the cytoplasm to the nucleus. The transfer is inhibited in the presence of IRF3.
Wathelet et al. (1998) identified a virus-activated factor (VAF) that binds to a regulatory element shared by different virus-inducible genes. VAF contains 2 members of the IRF family of transcriptional activator proteins, IRF3 and IRF7, and the transcriptional coactivator proteins p300 (602700) and CBP (600140). Remarkably, VAF and recombinant IRF3 and IRF7 proteins bind weakly to the IFNB gene promoter in vitro. However, in virus-infected cells, both proteins are recruited to the endogenous IFNB promoter as part of a protein complex that includes ATF2 (123811)/c-jun (165160) and NF-kappa-B (see 164011). These observations demonstrated the coordinate activation of multiple transcriptional activator proteins and their highly cooperative assembly into a transcriptional enhancer complex in vivo.
Au et al. (2001) showed that IRF7 lacking its N-terminal 236 residues exerted a dominant-negative (DN) effect on virus-induced expression of endogenous type I IFN genes. IFNA expression in response to virus infection required full-length IRF7, with the serines at positions 483 and 484 playing a crucial role. Amino acids 418 to 473 of IRF7 interacted with IRF3. Expression of the N-terminally truncated IRF7 DN protein resulted in a significant reduction of IRF7 and IRF3 binding to the IFNA1 promoter. Au et al. (2001) concluded that IRF3/IRF7 complexes are biologically active and are involved in virus-activated transcription of IFNA genes.
Sharma et al. (2003) demonstrated that IKKE (605048) and TANK-binding kinase-1 (TBK1; 604834) are components of the virus-activated kinase (VAK) that phosphorylate IRF3 (603734) and IRF7. They demonstrated an essential role for an IKK-related kinase pathway in triggering the host antiviral response to viral infection. Sharma et al. (2003) demonstrated that expression of IKKE or TBK1 is sufficient to induce phosphorylation of IRF3 and IRF7. This modification permits IRF3 dimerization and translocation to the nucleus, where it induces transcription of interferon and ISG56 genes.
Colina et al. (2008) showed that translational control of IRF7 is critical for induction of type I interferon (see 147570) production. In mouse embryonic fibroblasts lacking the translational repressors 4Ebp1 (602223) and 4Ebp2 (602224), the threshold for eliciting type I interferon production is lowered. Consequently, replication of encephalomyocarditis virus, vesicular stomatitis virus, influenza virus, and Sindbis virus is markedly suppressed. Furthermore, Colina et al. (2008) showed that mice with both 4Ebp1 and 4Ebp2 genes knocked out are resistant to vesicular stomatitis virus infection, and this correlates with an enhanced type I interferon production in plasmacytoid dendritic cells and the expression of interferon-regulated genes in the lungs. The enhanced type I interferon response of 4Ebp1 -/- 4Ebp2 -/- double knockout mouse embryonic fibroblasts is caused by upregulation of Irf7 mRNA translation. Colina et al. (2008) found that their findings highlighted the role of 4EBPs as negative regulators of type I interferon production, via translational repression of IRF7 mRNA.
Litvak et al. (2012) used an unbiased systems approach to predict that a member of the forkhead family of transcription factors, FOXO3 (602681), is a negative regulator of a subset of antiviral genes. This prediction was validated using macrophages isolated from Foxo3-null mice. Genomewide location analysis combined with gene deletion studies identified the IRF7 gene as a critical target of FOXO3. FOXO3 was identified as a negative regulator of IRF7 transcription. Litvak et al. (2012) further demonstrated that FOXO3, IRF7, and type I interferon form a coherent feed-forward regulatory circuit. Litvak et al. (2012) concluded their data suggested that the FOXO3-IRF7 regulatory circuit represents a novel mechanism for establishing the requisite set points in the interferon pathway that balances the beneficial effects and deleterious sequelae of the antiviral response.
Using single-cell RNA sequencing in mouse bone marrow-derived dendritic cells (BMDCs) stimulated with lipopolysaccharide (LPS) to investigate expression variability on a genomic scale, Shalek et al. (2013) observed extensive and theretofore unobserved bimodal variation in mRNA abundance and splicing patterns. They found that hundreds of key immune genes are bimodally expressed across cells, even genes that are very highly expressed at the population average. Moreover, splicing patterns demonstrated heterogeneity between cells. Shalek et al. (2013) identified a module of 137 highly variable yet coregulated antiviral response genes. Using cells from knockout mice, Shalek et al. (2013) showed that variability in this module may be propagated through an interferon feedback circuit, involving the transcriptional regulators Stat2 (600556) and Irf7. This finding demonstrated that while some of the observed bimodality could be attributed to closely related, yet distinct, known maturity states of BMDCs, other portions reflected differences in the usage of key regulatory circuits.
Immunodeficiency 39
In a 7-year-old French girl with immunodeficiency-39 (IMD39; 616345) manifest as life-threatening H1N1 influenza A infection, Ciancanelli et al. (2015) identified compound heterozygous mutations in the IRF7 gene (F410V, 605047.0001 and Q421X, 605047.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. In vitro studies and studies of patient cells showed impaired type I and type III interferon responses to influenza virus, as well as increased virus replication.
Associations Pending Confirmation
Heinig et al. (2010) reported the use of integrated genomewide approaches across 7 rat tissues to identify gene networks and the loci underlying their regulation. They defined an IRF7-driven inflammatory network (IDIN) enriched for viral response genes, which represented a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. Heinig et al. (2010) showed that Epstein-Barr virus-induced gene-2 (Ebi2, also known as Gpr183, 605741), which lies at this locus and controls B lymphocyte migration, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (see 222100), a macrophage-associated autoimmune disease, than randomly selected immune response genes (p = 8.85 x 10(-6)). The human locus controlling the IDIN was associated with the risk of type 1 diabetes at rs9585056 (p = 7.0 x 10(-10); odds ratio, 1.15), which was 1 of 5 SNPs in this region associated with EBI2 expression. Heinig et al. (2010) concluded that their data implicated IRF7 network genes and their regulatory locus in the pathogenesis of type 1 diabetes.
Honda et al. (2005) generated mice deficient in Irf7 by targeted disruption. Using Irf7-null mice, they showed that the transcription factor IRF7 is essential for the induction of IFN-alpha/beta genes via the virus-activated, MYD88 (602170)-independent pathway and the toll-like receptor (TLR)-activated, MYD88-dependent pathway. Viral induction of Myd88-independent Ifn-alpha/beta genes is severely impaired in Irf7-null fibroblasts. Irf7-null mice are consistently more vulnerable than Myd88-null mice to viral infection, and this correlates with marked decrease in serum interferon levels, indicating the importance of the IRF7-dependent induction of systemic interferon responses for innate antiviral immunity. Furthermore, robust induction of interferon production by activation of the Tlr9 (605474) subfamily in plasmacytoid dendritic cells was entirely dependent on Irf7, and this Myd88-Irf7 pathway governed the induction of CD8(+) T-cell responses. Honda et al. (2005) concluded that all elements of interferon responses, whether the systemic production of interferon in innate immunity or the local action of interferon from plasmacytoid dendritic cells in adaptive immunity, are controlled by IRF7.
Chen et al. (2013) observed highly increased viral titers, but no mortality over 30 days, in mice lacking both Irf3 and Irf7 following infection with Dengue virus type 2 (DENV2) compared with wildtype mice and mice lacking only Irf3 or Irf7. Viral burden was even higher in Ifnar1 (107450)-null mice, which died within 7 days of infection. Irf7 -/- mice and Irf3-/- Irf7-/- mice expressed significantly low levels of Ifna and Ifnb, but induction of Cxcl10 (147310) and Ifna2 (147562) was not impaired. Multiple other cytokines, including Ifng, were present at high levels in serum of Irf3-/- Irf7-/- mice within 24 hours, at which time DENV2 began to be cleared. DENV replication was restricted by Ifng, Cxcl10, and Cxcr3 (300574) in Irf3-/- Irf7-/- mice. Additionally, other Ifn-stimulated genes were induced independently of Irf3 and Irf7. Chen et al. (2013) concluded that IRF3 and IRF7 are required for early control of DENV infection, but that a late IRF3- and IRF7-independent pathway contributes to anti-DENV immunity.
In a 7-year-old French girl with immunodeficiency-39 (IMD39; 616345) manifest as life-threatening H1N1 influenza A infection, Ciancanelli et al. (2015) identified compound heterozygous mutations in the IRF7 gene: a c.1228T-G transversion (c.1228T-G, ENST00000397574), resulting in a phe410-to-val (F410V) substitution, and a c.1261C-T transition, resulting in a gln421-to-ter (Q421X; 605047.0002) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the dbSNP, 1000 Genomes Project, and Exome Sequencing Project (ESP6500) databases as well as 1,661 in-house control exomes. F410V was not found in public databases, whereas Q421X was found at a very low frequency (0.000008) in the Exome Aggregation Consortium database. Reporter assays showed that both mutations caused a loss of function. The truncated Q421X protein lacks the C-terminal serine residue required for phosphorylation and activation, whereas the F410V mutant protein showed abnormal localization to the cytoplasm rather than the nucleus. Patient white cells showed downregulation of innate immune genes at baseline, and failed to show induction of type I and type III interferon genes upon stimulation. Patient fibroblasts showed decreased IRF7 protein levels and increased replication of influenza A compared to controls. Ciancanelli et al. (2015) concluded that IRF7 deficiency disrupts the main function of plasmacytoid dendritic cells that produce antiviral interferons. The patient developed severe influenza at age 2.5 years. After recovery and subsequent flu vaccination, she had no other episodes. She had no detectable immunologic abnormalities of B or T cells, and did not have clinical infections caused by other viruses, although she was seropositive for several virus antibodies.
For discussion of the gln421-to-ter (Q421X) mutation (c.1261C-T, ENST00000397574) in the IRF7 gene that was found in compound heterozygous state in a patient with immunodeficiency-39 (IMD39; 616345) by Ciancanelli et al. (2015), see 605047.0001.
Au, W.-C., Moore, P. A., LaFleur, D. W., Tombal, B., Pitha, P. M. Characterization of the interferon regulatory factor-7 and its potential role in the transcription activation of interferon A genes. J. Biol. Chem. 273: 29210-29217, 1998. [PubMed: 9786932] [Full Text: https://doi.org/10.1074/jbc.273.44.29210]
Au, W.-C., Yeow, W.-S., Pitha, P. M. Analysis of functional domain of interferon regulatory factor 7 and its association with IRF-3. Virology 280: 273-282, 2001. [PubMed: 11162841] [Full Text: https://doi.org/10.1006/viro.2000.0782]
Chen, H.-W., King, K., Tu, J., Sanchez, M., Luster, A. D., Shresta, S. The roles of IRF-3 and IRF-7 in innate antiviral immunity against Dengue virus. J. Immun. 191: 4194-4201, 2013. [PubMed: 24043884] [Full Text: https://doi.org/10.4049/jimmunol.1300799]
Ciancanelli, M. J., Huang, S. X. L., Luthra, P., Garner, H., Itan, Y., Volpi, S., Lafaille, F. G., Trouillet, C., Schmolke, M., Albrecht, R. A., Israelsson, E., Lim, H. K., and 20 others. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science 348: 448-453, 2015. [PubMed: 25814066] [Full Text: https://doi.org/10.1126/science.aaa1578]
Colina, R., Costa-Mattioli, M., Dowling, R. J. O., Jaramillo, M., Tai, L.-H., Breitbach, C. J., Martineau, Y., Larsson, O., Rong, L., Svitkin, Y. V., Makrigiannis, A. P., Bell, J. C., Sonenberg, N. Translational control of the innate immune response through IRF-7. Nature 452: 323-328, 2008. [PubMed: 18272964] [Full Text: https://doi.org/10.1038/nature06730]
Heinig, M., Petretto, E., Wallace, C., Bottolo, L., Rotival, M., Lu, H., Li, Y., Sarwar, R., Langley, S. R., Bauerfeind, A., Hummel, O., Lee, Y.-A., and 33 others. A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467: 460-464, 2010. [PubMed: 20827270] [Full Text: https://doi.org/10.1038/nature09386]
Honda, K., Yanai, H., Negishi, H., Asagiri, M., Sato, M., Mizutani, T., Shimada, N., Ohba, Y., Takaoka, A., Yoshida, N., Taniguchi, T. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434: 772-777, 2005. [PubMed: 15800576] [Full Text: https://doi.org/10.1038/nature03464]
Litvak, V., Ratushny, A. V., Lampano, A. E., Schmitz, F., Huang, A. C., Raman, A., Rust, A. G., Bergthaler, A., Aitchison, J. D., Aderen, A. A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses. Nature 490: 421-425, 2012. [PubMed: 22982991] [Full Text: https://doi.org/10.1038/nature11428]
Shalek, A. K., Satija, R., Adiconis, X., Gertner, R. S., Gaublomme, J. T., Raychowdhury, R., Schwartz, S., Yosef, N., Malboeuf, C., Lu, D., Trombetta, J. J., Gennert, D., Gnirke, A., Goren, A., Hacohen, N., Levin, J. Z., Park, H., Regev, A. Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells. Nature 498: 236-240, 2013. [PubMed: 23685454] [Full Text: https://doi.org/10.1038/nature12172]
Sharma, S., tenOever, B. R., Grandvaux, N., Zhou, G.-P., Lin, R., Hiscott, J. Triggering the interferon antiviral response through an IKK-related pathway. Science 300: 1148-1151, 2003. [PubMed: 12702806] [Full Text: https://doi.org/10.1126/science.1081315]
Wathelet, M. G., Lin, C. H., Parekh, B. S., Ronco, L. V., Howley, P. M., Maniatis, T. Virus infection induces the assembly of coordinately activated transcription factors on the IFN-beta enhancer in vivo. Molec. Cell 1: 507-518, 1998. Note: Erratum: Molec. Cell 3: 813 only, 1999. [PubMed: 9660935] [Full Text: https://doi.org/10.1016/s1097-2765(00)80051-9]
Zhang, L., Pagano, J. S. IRF-7, a new interferon regulatory factor associated with Epstein Barr virus latency. Molec. Cell. Biol. 17: 5748-5757, 1997. [PubMed: 9315633] [Full Text: https://doi.org/10.1128/MCB.17.10.5748]