Signal transducer and activator of transcription 4 (STAT4) is atranscription factor belonging to theSTAT protein family, composed ofSTAT1,STAT2,STAT3, STAT4,STAT5A,STAT5B,STAT6.[5] STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient.[6] STAT proteins are a common part ofJanus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naiveCD4+ T cells[7] andIFN-γ production in response toIL-12.[8] There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma (IFN-γ )production downstream.[9]
Human as well murine STAT4 genes lie next toSTAT1 gene locus suggesting that the genes arose bygene duplication.[5]STAT proteins have six functionaldomains: 1.N-terminal interaction domain – crucial for dimerization of inactive STATs and nuclear translocation; 2.helical coiled coil domain – association with regulatory factors; 3. centralDNA-binding domain – binding to the enhancer region of IFN-γ activated sequence (GAS) family genes; 4. linker domain – assisting during the DNA binding process; 5. Src homology 2(SH2) domain – critical for specific binding to the cytokine receptor after tyrosine phosphorylation; 6.C-terminaltransactivation domain – triggering the transcriptional process.[10][11] The length of the protein is 748 amino acids, and the molecular weight is 85 941Dalton.[12]
Distribution of STAT4 is restricted tomyeloid cells,thymus andtestis.[5] In resting humanT cells it is expressed at very low levels, but its production is amplified byPHA stimulation.[8]
Pro-inflammatory cytokineIL-12 is produced in heterodimer form byB cells andantigen-presenting cells. Binding of IL-12 to IL-12R, which is composed of two different 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 pathway then inducesIFNγ production and Th1 differentiation. STAT4 is critical in promotion of antiviral response ofnatural killer (NK) cell by targeting of promotor regions of Runx1 and Runx3.[13]
Secreted by leukocytes, respectively fibroblasts, IFNα IFNβ together regulate antiviral immunity, cell proliferation and anti-tumor effects.[14] In viral infection signalling pathway, either of IFNα or β binds to IFN receptor (IFNAR), composed of IFNAR1 and IFNAR2, immediately followed by the phosphorylation of STAT1, STAT4 and IFN target genes.[15] During the initial phase of viral infection in NK cells, STAT1 activation is replaced by the activation of STAT4.
Monocytes, activated dendritic cells (DC) and macrophages stimulate the accumulation of IL-23 after exposure to molecules of Gram-positive/negative bacteria or viruses. Receptor for IL-23 contains IL12β1 and IL23R subunits, which upon binding of IL-23 promotes the phosphorylation STAT4. The presence of IL12β1 enables similar, although weaker downstream activity as compared to IL-12. During chronic inflammation, IL-23/STAT4 signalling pathway is involved in the induction of differentiation and expansion of Th17 pro-inflammatory T helper cells.[16]
Additionally, other cytokines like IL2, IL 27, IL35, IL18 and IL21 are known to activate STAT4.
In cells with progressively increasing expression of IL12 and IL6, SOCSs production and activity suppress cytokine signalling and phosphorylation of JAK-STAT pathways in anegative feedback loop.[17]
Other suppressors of the pathways are: protein inhibitor of activated STAT (PAIS) (regulation of transcriptional activity in the nucleus, observed in STAT4-DNA binding complex), 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 blocking the phosphorylation of STAT4) or microRNA (miRNA) (degradation of STAT4 mRNA and its post-transcriptional regulation).[11]
STAT4 is involved in several autoimmune and cancer diseases in animal models humans, significantly in the disease progression and pathology. STAT4 were significantly increased in patients withcolitis ulcerative[19] and skin T cells ofpsoriatic patients.[20] Moreover, STAT4 -/- mice developed less severeexperimental autoimmune encephalo-myelitis (EAE) than the wild type mice.[21][22]
^Ohtani K, Ohtsuka Y, Ikuse T, Baba Y, Yamakawa Y, Aoyagi Y, et al. (August 2010). "Increased mucosal expression of GATA-3 and STAT-4 in pediatric ulcerative colitis".Pediatrics International.52 (4):584–9.doi:10.1111/j.1442-200X.2009.03019.x.PMID20030749.S2CID21910658.
^Liang YL, Wu H, Shen X, Li PQ, Yang XQ, Liang L, et al. (September 2012). "Association of STAT4 rs7574865 polymorphism with autoimmune diseases: a meta-analysis".Molecular Biology Reports.39 (9):8873–82.doi:10.1007/s11033-012-1754-1.PMID22714917.S2CID10984779.
