interferon-stimulated gene

ISGs are genes whose expression can be stimulated by interferon, but may also be stimulated by other pathways. Interferons are a type of protein called a cytokine, which is produced in response to infection.{{cite journal | vauthors = Lazear HM, Schoggins JW, Diamond MS | title = Shared and Distinct Functions of Type I and Type III Interferons | journal = Immunity | volume = 50 | issue = 4 | pages = 907–923 | date = April 2019 | pmid = 30995506 | doi = 10.1016/j.immuni.2019.03.025|pmc=6839410 | doi-access = free }} When released, they signal to infected cells and other nearby cells that a pathogen is present.

This signal is passed from one cell to another by binding of the interferon to a cell surface receptor on a naïve cell.{{cite journal | vauthors = Hoffmann HH, Schneider WM, Rice CM | title = Interferons and viruses: an evolutionary arms race of molecular interactions | journal = Trends in Immunology | volume = 36 | issue = 3 | pages = 124–38 | date = March 2015 | pmid = 25704559 | doi = 10.1016/j.it.2015.01.004 | pmc = 4384471 }} The receptor and interferon are taken inside the cell while bound to initiate expression of ISGs.

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. The protein products of ISGs control pathogen infections.

Specifically, type I and type III interferons are antiviral cytokines, triggering ISGs that combat viral infections.{{cite journal | vauthors = Schoggins JW | title = Recent advances in antiviral interferon-stimulated gene biology | journal = F1000Research | volume = 7 | pages = 309 | date = 2018-03-12 | pmid = 29568506 | pmc = 5850085 | doi = 10.12688/f1000research.12450.1 | doi-access = free }} Type I interferons are also involved in bacterial infections; however, they can have both beneficial and harmful effects.{{cite journal | vauthors = Ivashkiv LB, Donlin LT | title = Regulation of type I interferon responses | journal = Nature Reviews. Immunology | volume = 14 | issue = 1 | pages = 36–49 | date = January 2014 | pmid = 24362405 | pmc = 4084561 | doi = 10.1038/nri3581 }} 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.{{cite journal | vauthors = Takaoka A, Yanai H | title = Interferon signalling network in innate defence | journal = Cellular Microbiology | volume = 8 | issue = 6 | pages = 907–22 | date = June 2006 | pmid = 16681834 | doi = 10.1111/j.1462-5822.2006.00716.x | s2cid = 2130730 | doi-access =}}

All ISG stimulation pathways result in the production of transcription factors. 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). Type II interferons produce a transcription factor called GAF, which binds to a promoter sequence called GAS. These interactions initiate gene expression. These pathways are also commonly initiated by a Toll-like receptor (TLR) on the cell surface. The number and type of ISGs expressed in response to infection is specific to the infecting pathogen.

The IFIT family of ISGs is located on chromosome 10 in humans and is homologous in mammals, birds, and fish. The IFIT family is commonly induced by type I and type III interferon. 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. 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. IFIT 1 and IFIT 2 directly bind Eukaryotic initiation factor 3,  which reduces more than 60% of protein translation in the targeted cell.

File:IFIT binding double-stranded triphosphate RNA.png

ISGs have a wide range of functions used to combat infection at all stages of a pathogen's lifestyle. 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.

Another ISG function is regulating interferon sensitivity of a cell. 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.

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.{{Cite journal |last1=de Veer |first1=Michael J. |last2=Holko |first2=Michelle |last3=Frevel |first3=Mathias |last4=Walker |first4=Eldon |last5=Der |first5=Sandy |last6=Paranjape |first6=Jayashree M. |last7=Silverman |first7=Robert H. |last8=Williams |first8=Bryan R. G. |date=2003 |title=Functional classification of interferon-stimulated genes identified using microarrays |journal=Journal of Leukocyte Biology |language=en |volume=69 |issue=6 |pages=912–920 |doi=10.1189/jlb.69.6.912 |pmid=11404376 |s2cid=1714991 |issn=0741-5400|doi-access=free }} Interferon stimulates genes that help active immune response and suppress infection at almost all stages of infection.

There are 21 known ISGs that inhibit RNA virus replication.{{Cite journal |last1=Yang |first1=Emily |last2=Li |first2=Melody M. H. |date=2020 |title=All About the RNA: Interferon-Stimulated Genes That Interfere With Viral RNA Processes |journal=Frontiers in Immunology |volume=11 |page=605024 |doi=10.3389/fimmu.2020.605024 |pmid=33362792 |pmc=7756014 |issn=1664-3224 |doi-access=free }} 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. 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.

There are 15 known ISG that help induce apoptosis. 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.{{Cite journal |last1=Chawla-Sarkar |first1=M. |last2=Lindner |first2=D. J. |last3=Liu |first3=Y.-F. |last4=Williams |first4=B. R. |last5=Sen |first5=G. C. |last6=Silverman |first6=R. H. |last7=Borden |first7=E. C. |date=2003-06-01 |title=Apoptosis and interferons: Role of interferon-stimulated genes as mediators of apoptosis |journal=Apoptosis |language=en |volume=8 |issue=3 |pages=237–249 |doi=10.1023/A:1023668705040 |pmid=12766484 |s2cid=29138124 |issn=1573-675X|doi-access=free }}

• Interferome

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Category:Cytokines