STAT4 explained

Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6.[1] STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient.[2] STAT proteins are a common part of Janus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive CD4+ T cells[3] and IFN-γ production in response to IL-12.[4] There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma (IFN-γ)production downstream.[5]

Structure

Human as well murine STAT4 genes lie next to STAT1 gene locus suggesting that the genes arose by gene duplication.[1] STAT proteins have six functional domains: 1. N-terminal interaction domain – crucial for dimerization of inactive STATs and nuclear translocation; 2.helical coiled coil domain –  association with regulatory factors; 3. central DNA-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-terminal transactivation domain – triggering the transcriptional process.[6] [7] The length of the protein is 748 amino acids, and the molecular weight is 85 941 Dalton.[8]

Expression

Distribution of STAT4 is restricted to myeloid cells, thymus and testis.[1] In resting human T cells it is expressed at very low levels, but its production is amplified by PHA stimulation.[4]

Cytokines activating STAT4

IL-12

Pro-inflammatory cytokine IL-12 is produced in heterodimer form by B cells and antigen-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 induces IFNγ production and Th1 differentiation. STAT4 is critical in promotion of antiviral response of natural killer (NK) cell by targeting of promotor regions of Runx1 and Runx3.[9]

IFNα and IFNβ

Secreted by leukocytes, respectively fibroblasts, IFNα IFNβ together regulate antiviral immunity, cell proliferation and anti-tumor effects.[10] 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.[11] During the initial phase of viral infection in NK cells, STAT1 activation is replaced by the activation of STAT4.

IL-23

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.[12]

Additionally, other cytokines like IL2, IL 27, IL35, IL18 and IL21 are known to activate STAT4.

Inhibitors of STAT4 signalling pathways

In cells with progressively increasing expression of IL12 and IL6, SOCSs production and activity suppress cytokine signalling and phosphorylation of JAK-STAT pathways in a negative feedback loop.[13]

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).

Target genes

STAT4 binds to hundreds of sites in the genome,[14] among others to the promoters of genes for cytokines (IFN-γ, TNF), receptors (IL18R1, IL12rβ2, IL18RAP), and signaling factors (MYD88).[14]

Disease

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 with colitis ulcerative[15] and skin T cells of psoriatic patients.[16] Moreover, STAT4 -/- mice developed less severe experimental autoimmune encephalo-myelitis (EAE) than the wild type mice.[17] [18]

Intronic single nucleotide polymorphism (SNP) mostly in third intron of the STAT4 has shown to be associated with immune dysregulation and autoimmunity including systemic lupus erythematosus (SLE)[19] and rheumatoid arthritis[20] as well as Sjögren's disease (SD),[21] systemic sclerosis,[22] psoriasis[23] and also type-1 diabetes.[24] High incident of STAT4 genetic polymorphisms and susceptibility to autoimmune diseases is a reason to consider the STAT4 as general autoimmune disease susceptibility locus.[25]

Further reading

Notes and References

  1. Yamamoto K, Quelle FW, Thierfelder WE, Kreider BL, Gilbert DJ, Jenkins NA, Copeland NG, Silvennoinen O, Ihle JN . 6 . Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation . Molecular and Cellular Biology . 14 . 7 . 4342–9 . July 1994 . 8007943 . 358805 . 10.1128/mcb.14.7.4342 .
  2. Darnell JE, Kerr IM, Stark GR . Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins . Science . 264 . 5164 . 1415–21 . June 1994 . 8197455 . 10.1126/science.8197455 . 1994Sci...264.1415D .
  3. Kaplan MH . STAT4: a critical regulator of inflammation in vivo . Immunologic Research . 31 . 3 . 231–42 . 2005 . 15888914 . 10.1385/IR:31:3:231 .
  4. Bacon CM, Petricoin EF, Ortaldo JR, Rees RC, Larner AC, Johnston JA, O'Shea JJ . 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 . 16 . 7307–11 . August 1995 . 7638186 . 41328 . 10.1073/pnas.92.16.7307 . 1995PNAS...92.7307B . free .
  5. Hoey T, Zhang S, Schmidt N, Yu Q, Ramchandani S, Xu X, Naeger LK, Sun YL, Kaplan MH . 6 . Distinct requirements for the naturally occurring splice forms Stat4alpha and Stat4beta in IL-12 responses . The EMBO Journal . 22 . 16 . 4237–48 . August 2003 . 12912921 . 175783 . 10.1093/emboj/cdg393 .
  6. Chang HC, Zhang S, Oldham I, Naeger L, Hoey T, Kaplan MH . STAT4 requires the N-terminal domain for efficient phosphorylation . The Journal of Biological Chemistry . 278 . 34 . 32471–7 . August 2003 . 12805384 . 10.1074/jbc.M302776200 . free .
  7. Yang C, Mai H, Peng J, Zhou B, Hou J, Jiang D . STAT4: an immunoregulator contributing to diverse human diseases . International Journal of Biological Sciences . 16 . 9 . 1575–1585 . 2020 . 32226303 . 7097918 . 10.7150/ijbs.41852 .
  8. Web site: STAT4 - Signal transducer and activator of transcription 4 - Homo sapiens (Human) - STAT4 gene & protein. www.uniprot.org. 2019-02-09.
  9. Rapp M, Lau CM, Adams NM, Weizman OE, O'Sullivan TE, Geary CD, Sun JC . Core-binding factor β and Runx transcription factors promote adaptive natural killer cell responses . Science Immunology . 2 . 18 . eaan3796 . December 2017 . 29222089 . 6265048 . 10.1126/sciimmunol.aan3796 .
  10. Li SF, Gong MJ, Zhao FR, Shao JJ, Xie YL, Zhang YG, Chang HY . Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection . Cellular Physiology and Biochemistry . 51 . 5 . 2377–2396 . 2018 . 30537741 . 10.1159/000495897 . free .
  11. Rönnblom L . The type I interferon system in the etiopathogenesis of autoimmune diseases . Upsala Journal of Medical Sciences . 116 . 4 . 227–37 . November 2011 . 22066971 . 3207297 . 10.3109/03009734.2011.624649 .
  12. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O'Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW . 6 . 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 . 11 . 5699–708 . June 2002 . 12023369 . 10.4049/jimmunol.168.11.5699 . free .
  13. Alexander WS . Suppressors of cytokine signalling (SOCS) in the immune system . Nature Reviews. Immunology . 2 . 6 . 410–6 . June 2002 . 12093007 . 10.1038/nri818 . 38009419 .
  14. Good SR, Thieu VT, Mathur AN, Yu Q, Stritesky GL, Yeh N, O'Malley JT, Perumal NB, Kaplan MH . 6 . Temporal induction pattern of STAT4 target genes defines potential for Th1 lineage-specific programming . Journal of Immunology . 183 . 6 . 3839–47 . September 2009 . 19710469 . 2748807 . 10.4049/jimmunol.0901411 .
  15. Ohtani K, Ohtsuka Y, Ikuse T, Baba Y, Yamakawa Y, Aoyagi Y, Fujii T, Kudo T, Nagata S, Shimizu T . 6 . Increased mucosal expression of GATA-3 and STAT-4 in pediatric ulcerative colitis . Pediatrics International . 52 . 4 . 584–9 . August 2010 . 20030749 . 10.1111/j.1442-200X.2009.03019.x . 21910658 .
  16. Eriksen KW, Lovato P, Skov L, Krejsgaard T, Kaltoft K, Geisler C, Ødum N . Increased sensitivity to interferon-alpha in psoriatic T cells . The Journal of Investigative Dermatology . 125 . 5 . 936–44 . November 2005 . 16297193 . 10.1111/j.0022-202X.2005.23864.x . free .
  17. Chitnis T, Najafian N, Benou C, Salama AD, Grusby MJ, Sayegh MH, Khoury SJ . Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis . The Journal of Clinical Investigation . 108 . 5 . 739–47 . September 2001 . 11544280 . 209380 . 10.1172/JCI12563 .
  18. Korn T, Bettelli E, Oukka M, Kuchroo VK . Vijay Kuchroo . IL-17 and Th17 Cells . Annual Review of Immunology . 27 . 485–517 . 2009 . 19132915 . 10.1146/annurev.immunol.021908.132710 .
  19. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, de Bakker PI, Le JM, Lee HS, Batliwalla F, Li W, Masters SL, Booty MG, Carulli JP, Padyukov L, Alfredsson L, Klareskog L, Chen WV, Amos CI, Criswell LA, Seldin MF, Kastner DL, Gregersen PK . 6 . STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus . The New England Journal of Medicine . 357 . 10 . 977–86 . September 2007 . 17804842 . 2630215 . 10.1056/NEJMoa073003 .
  20. Liang YL, Wu H, Shen X, Li PQ, Yang XQ, Liang L, Tian WH, Zhang LF, Xie XD . 6 . Association of STAT4 rs7574865 polymorphism with autoimmune diseases: a meta-analysis . Molecular Biology Reports . 39 . 9 . 8873–82 . September 2012 . 22714917 . 10.1007/s11033-012-1754-1 . 10984779 .
  21. Palomino-Morales RJ, Diaz-Gallo LM, Witte T, Anaya JM, Martín J . Influence of STAT4 polymorphism in primary Sjögren's syndrome . The Journal of Rheumatology . 37 . 5 . 1016–9 . May 2010 . 20360187 . 10.3899/jrheum.091007 . 40894904 . free .
  22. Rueda B, Broen J, Simeon C, Hesselstrand R, Diaz B, Suárez H, Ortego-Centeno N, Riemekasten G, Fonollosa V, Vonk MC, van den Hoogen FH, Sanchez-Román J, Aguirre-Zamorano MA, García-Portales R, Pros A, Camps MT, Gonzalez-Gay MA, Coenen MJ, Airo P, Beretta L, Scorza R, van Laar J, Gonzalez-Escribano MF, Nelson JL, Radstake TR, Martin J . 6 . The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype . Human Molecular Genetics . 18 . 11 . 2071–7 . June 2009 . 19286670 . 10.1093/hmg/ddp119 . free .
  23. Villarreal-Martínez A, Gallardo-Blanco H, Cerda-Flores R, Torres-Muñoz I, Gómez-Flores M, Salas-Alanís J, Ocampo-Candiani J, Martínez-Garza L . 6 . Candidate gene polymorphisms and risk of psoriasis: A pilot study . Experimental and Therapeutic Medicine . 11 . 4 . 1217–1222 . April 2016 . 27073425 . 4812537 . 10.3892/etm.2016.3066 .
  24. Santin I, Eizirik DL . Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and β-cell apoptosis . Diabetes, Obesity & Metabolism . 15 Suppl 3 . s3 . 71–81 . September 2013 . 24003923 . 10.1111/dom.12162 . 22297620 . free .
  25. Korman BD, Kastner DL, Gregersen PK, Remmers EF . STAT4: genetics, mechanisms, and implications for autoimmunity . Current Allergy and Asthma Reports . 8 . 5 . 398–403 . September 2008 . 18682104 . 2562257 . 10.1007/s11882-008-0077-8 .

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