An interferon-stimulated gene (ISG) is a

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

that can be expressed in response to stimulation by

interferon Interferons (IFNs, ) 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 the ...

. 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 The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is the ...

response. ISGs are commonly expressed in response to viral infection, but also during bacterial infection and in the presence of parasites.

Expression

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 Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

, which is produced in response to infection. 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. 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 The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals out ...

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 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 (also known as IL29, IL28A and IL28B respectively), and IFN-λ4. They were discovered in 2003. Their ...

. The protein products of ISGs control pathogen infections. Specifically, type I and type III interferons are antiviral cytokines, triggering ISGs that combat viral infections. Type I interferons are also involved in bacterial infections; however, they can have both beneficial and harmful effects. The type II interferon class only has one cytokine (

IFN-γ Interferon gamma (IFN-γ) 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 ...

), which has some antiviral activity, but is more important in establishing cellular immunity through activating macrophages and promoting major histocompatibility complex (MHC) class II. 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 Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are Bitopic protein, single-pass membrane-spanning Receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophage ...

(TLR) on the cell surface. The number and type of ISGs expressed in response to infection is specific to the infecting pathogen.

Function

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 Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed, mainly, by cells of ...

like a TLR or common signaling proteins like those found in the JAK-STAT pathway may be upregulated by interferons, making the cell more sensitive to interferons.

References

Cytokines {{Immunology-stub

Expression

Function

See also

References