Interferon-stimulated gene

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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]

Contents

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 IFIT binding double-stranded triphosphate RNA.png
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

Related Research Articles

<span class="mw-page-title-main">Interferon</span> Signaling proteins released by host cells in response to the presence of pathogens

Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

<span class="mw-page-title-main">Toll-like receptor</span> Class of immune system proteins

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Humans lack genes for TLR11, TLR12 and TLR13 and mice lack a functional gene for TLR10. The receptors TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles.

<span class="mw-page-title-main">Interferon gamma</span> InterPro Family

Interferon gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed interferon gamma release assay used to test for tuberculosis. In humans, the IFNG protein is encoded by the IFNG gene.

<span class="mw-page-title-main">Innate immune system</span> Immunity strategy in living beings

The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, prokaryotes, and invertebrates.

<i>Murine respirovirus</i> Sendai virus, virus of rodents

Murine respirovirus, formerly Sendai virus (SeV) and previously also known as murine parainfluenza virus type 1 or hemagglutinating virus of Japan (HVJ), is an enveloped, 150-200 nm–diameter, negative sense, single-stranded RNA virus of the family Paramyxoviridae. It typically infects rodents and it is not pathogenic for humans or domestic animals.

<span class="mw-page-title-main">Interleukin 29</span> Protein-coding gene in the species Homo sapiens

Interleukin-29 (IL-29) is a cytokine and it belongs to type III interferons group, also termed interferons λ (IFN-λ). IL-29 plays an important role in the immune response against pathogenes and especially against viruses by mechanisms similar to type I interferons, but targeting primarily cells of epithelial origin and hepatocytes.

The type III interferon group is a group of anti-viral cytokines, that consists of four IFN-λ (lambda) molecules called IFN-λ1, IFN-λ2, IFN-λ3, and IFN-λ4. They were discovered in 2003. Their function is similar to that of type I interferons, but is less intense and serves mostly as a first-line defense against viruses in the epithelium.

<span class="mw-page-title-main">Interferon-alpha/beta receptor</span> Heterodimeric receptor

The interferon-α/β receptor (IFNAR) is a virtually ubiquitous membrane receptor which binds endogenous type I interferon (IFN) cytokines. Endogenous human type I IFNs include many subtypes, such as interferons-α, -β, -ε, -κ, -ω, and -ζ.

<span class="mw-page-title-main">STAT1</span> Transcription factor and coding gene in humans

Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the STAT1 gene. It is a member of the STAT protein family.

<span class="mw-page-title-main">Toll-like receptor 7</span> Protein found in humans

Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds. It is a member of the toll-like receptor (TLR) family and detects single stranded RNA.

<span class="mw-page-title-main">STAT4</span> Protein-coding gene in the species Homo sapiens

Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient. STAT proteins are a common part of Janus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive CD4+ T cells and IFN-γ production in response to IL-12. There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma production downstream.

<span class="mw-page-title-main">STAT2</span> Protein-coding gene in Homo sapiens

Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the STAT2 gene. It is a member of the STAT protein family. This protein is critical to the biological response of type I interferons (IFNs). It functions as a transcription factor downstream of type I interferons. STAT2 sequence identity between mouse and human is only 68%.

<span class="mw-page-title-main">RIG-I</span> Mammalian protein found in humans

RIG-I is a cytosolic pattern recognition receptor (PRR) that can mediate induction of a type-I interferon (IFN1) response. RIG-I is an essential molecule in the innate immune system for recognizing cells that have been infected with a virus. These viruses can include West Nile virus, Japanese Encephalitis virus, influenza A, Sendai virus, flavivirus, and coronaviruses.

<span class="mw-page-title-main">IFNA2</span> Mammalian protein found in Homo sapiens

Interferon alpha-2 is a protein that in humans is encoded by the IFNA2 gene.

<span class="mw-page-title-main">Mitochondrial antiviral-signaling protein</span> Protein-coding gene in the species Homo sapiens

Mitochondrial antiviral-signaling protein (MAVS) is a protein that is essential for antiviral innate immunity. MAVS is located in the outer membrane of the mitochondria, peroxisomes, and mitochondrial-associated endoplasmic reticulum membrane (MAM). Upon viral infection, a group of cytosolic proteins will detect the presence of the virus and bind to MAVS, thereby activating MAVS. The activation of MAVS leads the virally infected cell to secrete cytokines. This induces an immune response which kills the host's virally infected cells, resulting in clearance of the virus.

Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.

RIG-I-like receptors are a type of intracellular pattern recognition receptor involved in the recognition of viruses by the innate immune system. RIG-I is the best characterized receptor within the RIG-I like receptor (RLR) family. Together with MDA5 and LGP2, this family of cytoplasmic pattern recognition receptors (PRRs) are sentinels for intracellular viral RNA that is a product of viral infection. The RLR receptors provide frontline defence against viral infections in most tissues.

<span class="mw-page-title-main">Guanylate-binding protein</span>

In molecular biology, the guanylate-binding proteins family is a family of GTPases that is induced by interferon (IFN)-gamma. GTPases induced by IFN-gamma are key to the protective immunity against microbial and viral pathogens. These GTPases are classified into three groups: the small 47-KD immunity-related GTPases (IRGs), the Mx proteins, and the large 65- to 67-kd GTPases. Guanylate-binding proteins (GBP) fall into the last class.

<span class="mw-page-title-main">Stimulator of interferon genes</span> Protein-coding gene in the species Homo sapiens

Stimulator of interferon genes (STING), also known as transmembrane protein 173 (TMEM173) and MPYS/MITA/ERIS is a protein that in humans is encoded by the STING1 gene.

IFIT proteins are produced in the human body and are supposed to confer immunity against viral infection. These proteins are generally produced during viral infection; Interferon (IFN) treatment; and during pathogen recognition by the immune system during infections.

References

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  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. 1 2 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. 1 2 3 4 5 6 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.
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  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. 1 2 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. 1 2 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.
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