ISRE

ISRE is the acronym for IFN-stimulated response elements. Interferon-stimulated response elements are short DNA sequences in the promoter region of certain genes. ISRE elements serve as binding sites for a family of transcription factors that are activated by interferons (INF-alpha, INF-beta). They are referred to as IFN regulatory factors (IRFs) (Heim MH 1999).

If, for example, a cell is infected by a virus, interferons are released. These bind to their respective receptor and activate the so-called JAK-STAT signaling pathway. In the process, certain transcription factors such as the ISGF3 complex migrate into the cell nucleus and bind to ISRE sequences in the DNA.

The association of interferon regulatory factor 9 (IRF-9) with STAT1-STAT2 heterodimers (ISGF3 complex = interferon-stimulated gene factor 3) or its association with STAT2 homodimers(STAT2/IRF9) in response to IFN-I directs these complexes to a specific group of target genes that contain the interferon-stimulated response element (ISRE) and to which they can bind (Michalska A et al. 2018).

Studies with knockout mice showed that IRF-4 plays a critical role in controlling the activation and homeostasis of immune responses and is crucial for the maturation of B cells. IRF-8\ICSBP is essential for myeloid cell differentiation into mature macrophages.

So far, nine cellular IFN regulatory factors (IRFs) have been identified. Some of the IRFs, such as IRF-1, IRF-2, IRF-3 and IRF-7, bind directly to ISRE elements, while others, such as IRF-4 and IRF-8, can only bind ISRE elements indirectly.

Thus, IRF8/ICSBP can associate with either IRF-1 or IRF-2 and form heterocomplexes that then bind to DNA. These protein-protein interactions are mediated by a conserved domain. This domain is called the IRF association domain (IAD). This IAD motif can be detected in all seven IRFs with the exception of IRF-1 and IRF-2.

1. Green R et al (2018) Interferon-stimulated genes: new platforms and computational approaches. Mamm Genome 29:593-602
2. Heim MH (1999) The Jak-STAT pathway: cytokine signalling from the receptor to the nucleus. J Recept Signal Transduct Res 19: 75-120.
3. Levraud JP et al (2019) IFN-stimulated genes in zebrafish and humans Define an Ancient Arsenal of Antiviral Immunity. J Immunol 203:3361-3373.
4. Manry J et al (2011) Evolutionary genetic dissection of human interferons. J Exp Med 208:2747-2759.
5. Michalska A et al. (2018) A Positive Feedback Amplifier Circuit That Regulates Interferon (IFN)-Stimulated Gene Expression and Controls Type I and Type II IFN Responses. Front Immunol 9:1135.
6. Sheikh SZ et al (2011) Characterization of an interferon-stimulated response element (ISRE) in the Il23a promoter. J Biol Chem. 286:1174-1180.