Interferon-stimulated gene

An interferon-stimulated gene (ISG) is a gene that can be expressed in response to stimulation by interferon.^[1][2] Interferons bind to receptors on the surface of a cell, initiating protein signaling pathways within the cell. This interaction leads to the expression of a subset of genes involved in the innate immune system response.^[1] ISGs are commonly expressed in response to viral infection, but also during bacterial infection and in the presence of parasites.^[2][1] It's currently estimated that 10% of the human genome is regulated by interferons (IFNs).^[3] Interferon stimulated genes can act as an initial response to pathogen invasion, slowing down viral replication and increasing expression of immune signaling complexes.^[4] There are three known types of interferon.^[5] With approximately 450 genes highly expressed in response to interferon type I.^[3] Type I interferon consists of INF-α, INF-β, INF-ω and is expressed in response to viral infection.^[6] ISGs induced by type I interferon are associated with viral replication suppression and increase expression of immune signaling proteins.^[7] Type II interferon consists only of INF-γ and is associated with controlling intracellular pathogens and tumor suppressor genes. Type III interferon consists of INF-λ and is associated with viral immune response and is key in anti-fungal neutrophil response.^[8]

Expression

ISGs are genes whose expression can be stimulated by interferon, but may also be stimulated by other pathways.^[1] Interferons are a type of protein called a cytokine, which is produced in response to infection.^[9] When released, they signal to infected cells and other nearby cells that a pathogen is present.^[9]

This signal is passed from one cell to another by binding of the interferon to a cell surface receptor on a naïve cell.^[10] The receptor and interferon are taken inside the cell while bound to initiate expression of ISGs.^[10]

Interferon activation of ISGs uses the JAK-STAT signaling pathway to induce transcription of ISGs. ISGs can be divided based on what class of interferon they are activated by: type I, type II, or type III interferon.^[1] The protein products of ISGs control pathogen infections.

Specifically, type I and type III interferons are antiviral cytokines, triggering ISGs that combat viral infections.^[11] Type I interferons are also involved in bacterial infections; however, they can have both beneficial and harmful effects.^[12] The type II interferon class only has one cytokine (IFN-γ), which has some antiviral activity, but is more important in establishing cellular immunity through activating macrophages and promoting major histocompatibility complex (MHC) class II.^[13]

All ISG stimulation pathways result in the production of transcription factors.^[2][10] Type I and type III interferons produce a protein complex called ISGF3, which acts as a transcription factor, and binds to a promoter sequence called ISRE (interferon stimulated response element).^[2][10] Type II interferons produce a transcription factor called GAF, which binds to a promoter sequence called GAS.^[2][10] These interactions initiate gene expression.^[1] These pathways are also commonly initiated by a Toll-like receptor (TLR) on the cell surface.^[2] The number and type of ISGs expressed in response to infection is specific to the infecting pathogen.^[2]

Family of Interferon stimulated genes

IFIT Family of Interferon stimulated genes

The IFIT family of ISGs is located on chromosome 10 in humans and is homologous in mammals, birds, and fish.^[5] The IFIT family is commonly induced by type I and type III interferon.^[3][5] IFIT gene expression has been observed in response to both DNA and RNA viral infection. IFIT genes suppress viral infection primarily by limiting viral RNA and DNA replication.^[5] IFIT proteins 1,2,3 and 5 can bind directly to double-stranded triphosphate RNA. These IFIT proteins form a complex that destroys the viral RNA.^[3][5] IFIT 1 and IFIT 2 directly bind Eukaryotic initiation factor 3,  which reduces more than 60% of protein translation in the targeted cell.^[5]

IFIT proteins binding to double-stranded triphosphate RNA and degrading the RNA

Function

ISGs have a wide range of functions used to combat infection at all stages of a pathogen's lifestyle.^[1] For a viral infection, examples include: prohibiting entry of the virus into uninfected cells, stopping viral replication, and preventing the virus from leaving an infected cell.^[1]

Another ISG function is regulating interferon sensitivity of a cell.^[1] The expression of pattern recognition receptors like a TLR or common signaling proteins like those found in the JAK-STAT pathway may be up regulated by interferons, making the cell more sensitive to interferons.^[10]

As such a large portion of the human genome is associated with interferon ISG have a broad range of functions. ISG are essential for fighting off viral bacterial and parasitic pathogens.^[14] Interferon stimulates genes that help active immune response and suppress infection at almost all stages of infection.^[3]

inhibition of viral RNA

There are 21 known ISGs that inhibit RNA virus replication.^[15] Primarily ISG bind to and degrade RNA to prevent viral instructions from being translated into viral proteins. These ISG can specifically target double stranded triphosphate RNA which is distinct from single stranded RNA present in human cells.^[3] ISG can also non specifically target mRNA and destroy it. Cell wide mRNA degradation prevents both viral and host proteins from being produced. The mRNA of INF-α and other key immune proteins are resistant to this cell wide degradation to allow immune signals to continue while translation is inhibited.^[15]

Apoptotic effects

There are 15 known ISG that help induce apoptosis.^[16] It is likely that none of these genes trigger apoptosis alone but their expression has been linked to apoptosis. Higher expression of ISG make the cell more susceptible to natural killer cells.^[16]

See also

• Interferome

References

1. Schneider WM, Chevillotte MD, Rice CM (2014-03-21). "Interferon-stimulated genes: a complex web of host defenses". Annual Review of Immunology. 32 (1): 513–45. doi:10.1146/annurev-immunol-032713-120231. PMC 4313732. PMID 24555472.
2. Sen GC, Sarkar SN (2007). "The Interferon-Stimulated Genes: Targets of Direct Signaling by Interferons, Double-Stranded RNA, and Viruses". Interferon: The 50th Anniversary. Current Topics in Microbiology and Immunology. Vol. 316. pp. 233–50. doi:10.1007/978-3-540-71329-6_12. ISBN 978-3-540-71328-9. PMID 17969451.
3. Schoggins, John W. (2019-09-29). "Interferon-Stimulated Genes: What Do They All Do?". Annual Review of Virology. 6 (1): 567–584. doi:10.1146/annurev-virology-092818-015756. ISSN 2327-056X. PMID 31283436. S2CID 195844135.
4. Wang, Wenshi; Xu, Lei; Su, Junhong; Peppelenbosch, Maikel P.; Pan, Qiuwei (2017-07-01). "Transcriptional Regulation of Antiviral Interferon-Stimulated Genes". Trends in Microbiology. 25 (7): 573–584. doi:10.1016/j.tim.2017.01.001. ISSN 0966-842X. PMC 7127685. PMID 28139375. S2CID 3995163.
5. Zhou, Xiang; Michal, Jennifer J.; Zhang, Lifan; Ding, Bo; Lunney, Joan K.; Liu, Bang; Jiang, Zhihua (2013). "Interferon Induced IFIT Family Genes in Host Antiviral Defense". International Journal of Biological Sciences. 9 (2): 200–208. doi:10.7150/ijbs.5613. ISSN 1449-2288. PMC 3584916. PMID 23459883. S2CID 17545167.
6. Levy, David E; Marié, Isabelle J; Durbin, Joan E (December 2011). "Induction and function of type I and III interferon in response to viral infection". Current Opinion in Virology. 1 (6): 476–486. doi:10.1016/j.coviro.2011.11.001. ISSN 1879-6257. PMC 3272644. PMID 22323926.
7. Schoenborn, Jamie R.; Wilson, Christopher B. (2007), Regulation of Interferon-γ During Innate and Adaptive Immune Responses, Advances in Immunology, vol. 96, Elsevier, pp. 41–101, doi:10.1016/s0065-2776(07)96002-2, ISBN 9780123737090, PMID 17981204
8. Gaffen, Sarah (2017-10-11). "Faculty Opinions recommendation of Type III interferon is a critical regulator of innate antifungal immunity". doi:10.3410/f.731931654.793537605. {{cite journal}}: Cite journal requires |journal= (help)
9. Lazear HM, Schoggins JW, Diamond MS (April 2019). "Shared and Distinct Functions of Type I and Type III Interferons". Immunity. 50 (4): 907–923. doi:10.1016/j.immuni.2019.03.025. PMC 6839410. PMID 30995506.
10. Hoffmann HH, Schneider WM, Rice CM (March 2015). "Interferons and viruses: an evolutionary arms race of molecular interactions". Trends in Immunology. 36 (3): 124–38. doi:10.1016/j.it.2015.01.004. PMC 4384471. PMID 25704559.
11. Schoggins JW (2018-03-12). "Recent advances in antiviral interferon-stimulated gene biology". F1000Research. 7: 309. doi:10.12688/f1000research.12450.1. PMC 5850085. PMID 29568506.
12. Ivashkiv LB, Donlin LT (January 2014). "Regulation of type I interferon responses". Nature Reviews. Immunology. 14 (1): 36–49. doi:10.1038/nri3581. PMC 4084561. PMID 24362405.
13. Takaoka A, Yanai H (June 2006). "Interferon signalling network in innate defence". Cellular Microbiology. 8 (6): 907–22. doi:10.1111/j.1462-5822.2006.00716.x. PMID 16681834. S2CID 2130730.
14. de Veer, Michael J.; Holko, Michelle; Frevel, Mathias; Walker, Eldon; Der, Sandy; Paranjape, Jayashree M.; Silverman, Robert H.; Williams, Bryan R. G. (2003). "Functional classification of interferon-stimulated genes identified using microarrays". Journal of Leukocyte Biology. 69 (6): 912–920. doi:10.1189/jlb.69.6.912. ISSN 0741-5400. PMID 11404376. S2CID 1714991.
15. Yang, Emily; Li, Melody M. H. (2020). "All About the RNA: Interferon-Stimulated Genes That Interfere With Viral RNA Processes". Frontiers in Immunology. 11: 605024. doi:10.3389/fimmu.2020.605024. ISSN 1664-3224. PMC 7756014. PMID 33362792.
16. Chawla-Sarkar, M.; Lindner, D. J.; Liu, Y.-F.; Williams, B. R.; Sen, G. C.; Silverman, R. H.; Borden, E. C. (2003-06-01). "Apoptosis and interferons: Role of interferon-stimulated genes as mediators of apoptosis". Apoptosis. 8 (3): 237–249. doi:10.1023/A:1023668705040. ISSN 1573-675X. PMID 12766484. S2CID 29138124.