Interferon Regulatory Factor Family

The interferon regulatory factor family is a family of interferon (IFN) regulatory factors (IRFs). They are transcription factors that play a central role in the regulation of the immune system, for example in the transcription of IFN genes and IFN-stimulated genes. Members of the IRF family are characterized by a conserved N-terminal DNA binding domain containing tryptophan (W) repeats.

In humans, the IRF family consists of 9 members (IFR1-IFR9). Each protein has a specific function, although there are overlaps in the functional areas.

IRF proteins are characterized by common structural features:

• DNA-binding domain (DBD): Highly conserved at the N-terminus; recognizes specific DNA sequences called Interferon-Stimulated Response Elements (ISRE).
• IRF-associated domain (IAD): At the C-terminus, important for protein-protein interactions (e.g. with other IRFs or with co-activators such as CBP/p300).
• Some IRFs have repressive functions, others are activators of gene expression.

/en/internal-medicine/irf5-gene-160218.amp" title="IRF5 geneThefunctions of the IRF family can be summarized as follows:

A.Antiviral immune response:

• IRF3 and IRF7 are critical for the induction of type I interferons (IFN-α and IFN-β) after viral infection.
• IRF3 is directly activated by virus sensing (via RIG-I/MAVS or cGAS/STING). IFR3 is constitutively expressed in a variety of tissues. The IRF-3 gene encodes a 50 kDa protein that specifically binds to the IFN-stimulated response element (ISRE).
• IRF7 is upregulated in plasma cells (especially pDCs) and enhances IFN production. Interferon regulatory factor 7 has been shown to play a role in the transcriptional activation of virus-inducible cellular genes, such as in the innate immune response against DNA and RNA viruses. The inducible expression of IRF7 is largely restricted to lymphoid tissue. IRF7 is an important transcriptional regulator of type I interferon (IFN)-dependent immune responses and plays a crucial role in the innate immune response against DNA and RNA viruses. The protein exists in an inactive form in the cytoplasm of uninfected cells and is phosphorylated and upregulated by the kinases IKBKE and TBK1 following viral infection as a result of double-stranded RNA (dsRNA) or Toll-like receptor (TLR) signaling. This results in a conformational change that leads to its dimerization and nuclear localization, where it can activate transcription of type I IFN and ISG genes together with other coactivators. IRF7 can activate various gene expression programs in macrophages and regulate the anti-tumor properties of primary macrophages.
• IRF9, together with STAT1 and STAT2, forms the ISGF3 complex, which activates interferon-stimulated genes (ISGs). IRF9 plays an essential role in antiviral immunity and mediates signaling through type I IFNs (IFN-alpha|IFN-beta). IRF9 combines with the phosphorylated STAT1/STAT2 dimer to form a protein complex called transcription factor ISGF3, which can enter the cell nucleus. ISGF3 binds to the IFN-stimulated response element (ISRE) to activate the transcription of interferon-stimulated genes that put the cell into an antiviral state. If this activation pathway is disrupted, the cell becomes susceptible to infection, particularly against viral pathogens.

B. Regulation of the innate and adaptive immune response

IRF4 and IRF8 are important for the differentiation of immune cells:

• IRF8 is essential for the development of dendritic cells and macrophages. The IRF8 gene encodes a protein, the Interferon Consensus Sequence-Binding Protein (ICSBP). The transcription factor IRF8 has been identified as an AML-specific susceptibility gene in humans. IRF8 is upregulated in a subset of AML cells. Thus, high IRF8 expression is associated with a poorer prognosis of patients (Liss F et al. 2021). IRF8 regulates important signaling molecules such as the kinases SRC and FAK, the transcription factors RUNX1 and IRF5 as well as the cell cycle regulator cyclin D1.IRF8 could serve as a biomarker and potential molecular target in a subset of human AML in the future.
• IRF4 controls the differentiation of T helper cells (Th2, Th17) and B cell responses.

  IRF4 is lymphocyte-specific and negatively regulates Toll-like receptor (TLR) signaling, which is central to the activation of the innate and adaptive immune system. IRF4 binds to the interferon-stimulated response element (ISRE) of the MHC class I promoter. It binds to the enhancer of the immunoglobulin lambda light chain. IRF4 is involved in CD8(+) differentiation of dendritic cells.

• IRF5 activates proinflammatory genes in macrophages (e.g. TNF-alpha, interleukin-6).
• IRF6 plays a role in the regulation of keratinocyte proliferation and differentiation.

C. Tumor suppression and cell cycle control

IRF1 is a tumor suppressor:

• Promotes apoptosis and suppresses cell proliferation.
• Regulates genes such as p21 or Fas.
• IRF2 can act antagonistically to IRF1 and often acts as a transcriptional repressor.

3. role in diseases

• Autoimmunity: Dysregulation of IRFs, especially IRF5 and IRF7, is associated with lupus erythematosus and other autoimmune diseases.
• Viral infections: Defects in IRF3 or IRF7 lead to increased susceptibility to viruses such as influenza or herpes viruses.
• Tumor development: IRF1 deficiency or IRF4 overexpression is observed in various tumors (e.g. multiple myeloma).

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