STAT4

STAT4 is the acronym for "Signal transducer and activator of transcription 4". STAT4 is a transcription factor that belongs to the STAT family of proteins(STAT1, STAT2, STAT3, STAT5A, STAT5B, and STAT6) ( Darnell JE et al 1994).

STAT proteins are key activators of gene transcription that bind to DNA in response to cytokine gradients. STAT proteins are a common part of Janus kinase (JAK) signaling pathways activated by cytokines.STAT4 is required for Th1 cell development from naive CD4+ T cells and IFN-γ production in response to IL-12 (Bacon CM et al 1995).

There are two known STAT4 transcripts, STAT4α and STAT4β, which differ in the level of downstream interferon-gamma (IFN-γ) production.

Both the human and murine nSTAT4 genes are located adjacent to the STAT1 gene locus. This proximity suggests that the genes arose by gene duplication (Yamamoto K et al. 1994).

STAT proteins have six functional domains (Yang C et al. 2020):

• N-terminal interaction domain - critical for dimerization of inactive STATs and nuclear translocation;
• helical coiled coil domain - association with regulatory factors.
• Central DNA binding domain - binding to the enhancer region of IFN-γ-activated sequence (GAS) family genes.
• Linker domain - assisting in the DNA binding process.
• Src homology 2 domain (SH2 domain) - critical for specific binding to cytokine receptor after tyrosine phosphorylation
• C-terminal transactivation domain - triggering the transcription process.

STAT4 expression is restricted to myeloid cells, thymus and testis.[5] It is expressed at very low levels in resting human T cells, but its production is enhanced by PHA stimulation (Yamamoto K et al 1994).

STAT4 activating cytokines

• IL-12: The proinflammatory cytokine IL-12 is produced in the form of a heterodimer by B cells and antigen-presenting cells. Binding of IL-12 to IL-12R, which consists of two distinct subunits (IL12Rβ1 and IL12Rβ2), leads to the interaction of IL12Rβ1 and IL12Rβ2 with JAK2 and TYK2, which is followed by phosphorylation of STAT4 tyrosine 693. The signaling pathway then induces IFNγ production and Th1 differentiation. STAT4 is critical for promoting the antiviral response of natural killer (NK) cells by targeting the promoter regions of Runx1 and Runx3 (Rapp M et al. 2017).
• IFNα and INFβ: In the viral infection signaling pathway, either IFNα or β binds to the IFN receptor (IFNAR), which is composed of IFNAR1 and IFNAR2, immediately followed by phosphorylation of STAT1, STAT4, and IFN target genes.During the initial phase of viral infection in NK cells, activation of STAT1 is replaced by activation of STAT4 (Rönnblom L 2011).
• Il-23: Monocytes, activated dendritic cells (DC) and macrophages stimulate the accumulation of IL-23 after exposure to molecules from Gram-positive/negative bacteria or viruses. The receptor for IL-23 contains the IL12β1 and IL23R subunits, which promote phosphorylation of STAT4 upon binding of IL-23. During chronic inflammation, the IL-23/STAT4 pathway is involved in the induction of differentiation and expansion of proinflammatory Th17 T helper cells (Parham C et al 2002).Furthermore, IL2, IL 27, IL35, IL18 and IL21 are known to activate STAT4.

Inhibitors of STAT4 signaling:

• In cells with progressively increasing expression of IL12 and IL6, the production and activity of SOCSs in a negative feedback loop suppresses cytokine signaling and phosphorylation of the JAK-STAT pathway (Alexander WS 2002).

Other pathway suppressors include:

• Protein inhibitor of activated STAT (PAIS) (regulating transcriptional activity in the nucleus).
• Protein tyrosine phosphatase (PTP) (removal of phosphate groups from phosphorylated tyrosine in JAK/STAT pathway proteins).
• STAT-interacting LIM protein (SLIM) (STAT ubiquitin E3 ligase that blocks phosphorylation of STAT4)
• MicroRNA (miRNA) (degradation of STAT4 mRNA and its post-transcriptional regulation).

Target genes: STAT4 binds to a very large number of sites in the genome, including the promoters of genes for cytokines(IFN-γ, TNF), receptors(IL18R1, IL12rβ2, IL18RAP) and signalling factors(MYD88) (Good SR et al. 2009).

STAT4 is significantly involved in disease progression and pathology in several autoimmune and cancer diseases in animal models and humans. STAT4 were significantly increased in patients with ulcerative colitis and in lesional T cells from psoriasis patients (Eriksen KW et al 2005).

Furthermore, genetic STAT4 polymorphisms have been shown to be associated with immune dysregulation and autoimmunity, including systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren's syndrome, systemic sclerosis, psoriasis, and type 1 diabetes.

The high incidence of STAT4 genetic polymorphisms and susceptibility to autoimmune diseases is one reason to consider STAT4 as a general "susceptibility locus" for autoimmune diseases (Korman BD et al. (2008).

1. Alexander WS (2002) Suppressors of cytokine signalling (SOCS) in the immune system. Nature Reviews. Immunology 2: 410-416.
2. Darnell JE et al (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 264: 1415–1421.
3. Bacon CM et al. (1995) Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes. Proceedings of the National Academy of Sciences of the United States of America 92: 7307-7311.
4. Eriksen KW et al. (2005) Increased sensitivity to interferon-alpha in psoriatic T cells. The Journal of Investigative Dermatology 125: 936-944.
5. Good SR et al (2009) Temporal induction pattern of STAT4 target genes defines potential for Th1 lineage-specific programming. Journal of Immunology 183: 3839-3847.
6. Korman BD et al. (2008) STAT4: genetics, mechanisms, and implications for autoimmunity". Current Allergy and Asthma Reports 8: 398-403.
7. Parham C et al (2002) A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. Journal of Immunology 168: 5699-5708.
8. Rapp M et al. (2017) Core-binding factor β and Runx transcription factors promote adaptive natural killer cell responses. Science Immunology 2: eaan3796.
9. Rönnblom L (2011). The type I interferon system in the etiopathogenesis of autoimmune diseases. Upsala Journal of Medical Sciences116: 227-237.
10. Yamamoto K et al. (1994) Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation. Molecular and Cellular Biology14: 4342-4349.
11. Yang C et al. (2020) STAT4: an immunoregulator contributing to diverse human diseases. International Journal of Biological Sciences 16: 1575-1585.