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{{Infobox_gene}}
{{Infobox_gene}}


'''Signal transducer and activator of transcription 4''' ('''STAT4''') is a [[transcription factor]] belonging to the [[STAT protein]] family, composed of [[STAT1]], [[STAT2]], [[STAT3]], [[STAT5A]], [[STAT5B]], [[STAT6]].<ref name="1 Yamamoto 1994">{{cite journal | vauthors = Yamamoto K, Quelle FW, Thierfelder WE, Kreider BL, Gilbert DJ, Jenkins NA, Copeland NG, Silvennoinen O, Ihle JN | display-authors = 6 | title = Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation | journal = Molecular and Cellular Biology | volume = 14 | issue = 7 | pages = 4342–9 | date = July 1994 | pmid = 8007943 | pmc = 358805 | doi = 10.1128/mcb.14.7.4342 }}</ref> STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient.<ref>{{cite journal | vauthors = Darnell JE, Kerr IM, Stark GR | title = Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins | journal = Science | volume = 264 | issue = 5164 | pages = 1415–21 | date = June 1994 | pmid = 8197455 | doi = 10.1126/science.8197455 | bibcode = 1994Sci...264.1415D }}</ref> STAT proteins are a common part of [[JAK-STAT signaling pathway|Janus kinase]] (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive [[T helper cell|CD4+ T cells]]<ref name="2 Kaplan 2005">{{cite journal | vauthors = Kaplan MH | title = STAT4: a critical regulator of inflammation in vivo | journal = Immunologic Research | volume = 31 | issue = 3 | pages = 231–42 | year = 2005 | pmid = 15888914 | doi = 10.1385/IR:31:3:231 | url = https://zenodo.org/record/894708 }}</ref> and [[Interferon-gamma|IFN-γ]] production in response to [[Interleukin 12|IL-12]].<ref name="3 Bacon 1995">{{cite journal | vauthors = Bacon CM, Petricoin EF, Ortaldo JR, Rees RC, Larner AC, Johnston JA, O'Shea JJ | title = Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 16 | pages = 7307–11 | date = August 1995 | pmid = 7638186 | pmc = 41328 | doi = 10.1073/pnas.92.16.7307 | bibcode = 1995PNAS...92.7307B | doi-access = free }}</ref> There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma (IFN-γ )production downstream.<ref>{{cite journal | vauthors = Hoey T, Zhang S, Schmidt N, Yu Q, Ramchandani S, Xu X, Naeger LK, Sun YL, Kaplan MH | display-authors = 6 | title = Distinct requirements for the naturally occurring splice forms Stat4alpha and Stat4beta in IL-12 responses | journal = The EMBO Journal | volume = 22 | issue = 16 | pages = 4237–48 | date = August 2003 | pmid = 12912921 | pmc = 175783 | doi = 10.1093/emboj/cdg393 }}</ref>
'''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]].<ref name="1 Yamamoto 1994">{{cite journal | vauthors = Yamamoto K, Quelle FW, Thierfelder WE, Kreider BL, Gilbert DJ, Jenkins NA, Copeland NG, Silvennoinen O, Ihle JN | display-authors = 6 | title = Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation | journal = Molecular and Cellular Biology | volume = 14 | issue = 7 | pages = 4342–9 | date = July 1994 | pmid = 8007943 | pmc = 358805 | doi = 10.1128/mcb.14.7.4342 }}</ref> STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient.<ref>{{cite journal | vauthors = Darnell JE, Kerr IM, Stark GR | title = Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins | journal = Science | volume = 264 | issue = 5164 | pages = 1415–21 | date = June 1994 | pmid = 8197455 | doi = 10.1126/science.8197455 | bibcode = 1994Sci...264.1415D }}</ref> STAT proteins are a common part of [[JAK-STAT signaling pathway|Janus kinase]] (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive [[T helper cell|CD4+ T cells]]<ref name="2 Kaplan 2005">{{cite journal | vauthors = Kaplan MH | title = STAT4: a critical regulator of inflammation in vivo | journal = Immunologic Research | volume = 31 | issue = 3 | pages = 231–42 | year = 2005 | pmid = 15888914 | doi = 10.1385/IR:31:3:231 | url = https://zenodo.org/record/894708 }}</ref> and [[Interferon-gamma|IFN-γ]] production in response to [[Interleukin 12|IL-12]].<ref name="3 Bacon 1995">{{cite journal | vauthors = Bacon CM, Petricoin EF, Ortaldo JR, Rees RC, Larner AC, Johnston JA, O'Shea JJ | title = Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 16 | pages = 7307–11 | date = August 1995 | pmid = 7638186 | pmc = 41328 | doi = 10.1073/pnas.92.16.7307 | bibcode = 1995PNAS...92.7307B | doi-access = free }}</ref> There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma (IFN-γ )production downstream.<ref>{{cite journal | vauthors = Hoey T, Zhang S, Schmidt N, Yu Q, Ramchandani S, Xu X, Naeger LK, Sun YL, Kaplan MH | display-authors = 6 | title = Distinct requirements for the naturally occurring splice forms Stat4alpha and Stat4beta in IL-12 responses | journal = The EMBO Journal | volume = 22 | issue = 16 | pages = 4237–48 | date = August 2003 | pmid = 12912921 | pmc = 175783 | doi = 10.1093/emboj/cdg393 }}</ref>


== Structure ==
== Structure ==


Human as well murine STAT4 genes lie next to [[STAT1]] gene locus suggesting that the genes arose by [[gene duplication]].<ref name="1 Yamamoto 1994"/> [[STAT protein]]s have six functional [[protein domain|domains]]: 1. [[N-terminus|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|(SH2) domai]]<nowiki/>n – critical for specific binding to the cytokine receptor after tyrosine phosphorylation; 6. [[C-terminus|C-terminal]] [[transactivation domain]] – triggering the transcriptional process.<ref name="4 Chang 2003">{{cite journal | vauthors = Chang HC, Zhang S, Oldham I, Naeger L, Hoey T, Kaplan MH | title = STAT4 requires the N-terminal domain for efficient phosphorylation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 34 | pages = 32471–7 | date = August 2003 | pmid = 12805384 | doi = 10.1074/jbc.M302776200 | doi-access = free }}</ref><ref name=":0">{{cite journal | vauthors = Yang C, Mai H, Peng J, Zhou B, Hou J, Jiang D | title = STAT4: an immunoregulator contributing to diverse human diseases | journal = International Journal of Biological Sciences | volume = 16 | issue = 9 | pages = 1575–1585 | date = 2020 | pmid = 32226303 | pmc = 7097918 | doi = 10.7150/ijbs.41852 }}</ref> The length of the protein is 748 amino acids, and the molecular weight is 85 941 [[Atomic mass unit|Dalton]].<ref>{{Cite web|url=https://www.uniprot.org/uniprot/Q14765|title=STAT4 - Signal transducer and activator of transcription 4 - Homo sapiens (Human) - STAT4 gene & protein|website=www.uniprot.org|access-date=2019-02-09}}</ref>
Human as well murine STAT4 genes lie next to [[STAT1]] gene locus suggesting that the genes arose by [[gene duplication]].<ref name="1 Yamamoto 1994"/> [[STAT protein]]s have six functional [[protein domain|domains]]: 1. [[N-terminus|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|(SH2) domain]] – critical for specific binding to the cytokine receptor after tyrosine phosphorylation; 6. [[C-terminus|C-terminal]] [[transactivation domain]] – triggering the transcriptional process.<ref name="4 Chang 2003">{{cite journal | vauthors = Chang HC, Zhang S, Oldham I, Naeger L, Hoey T, Kaplan MH | title = STAT4 requires the N-terminal domain for efficient phosphorylation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 34 | pages = 32471–7 | date = August 2003 | pmid = 12805384 | doi = 10.1074/jbc.M302776200 | doi-access = free }}</ref><ref name=":0">{{cite journal | vauthors = Yang C, Mai H, Peng J, Zhou B, Hou J, Jiang D | title = STAT4: an immunoregulator contributing to diverse human diseases | journal = International Journal of Biological Sciences | volume = 16 | issue = 9 | pages = 1575–1585 | date = 2020 | pmid = 32226303 | pmc = 7097918 | doi = 10.7150/ijbs.41852 }}</ref> The length of the protein is 748 amino acids, and the molecular weight is 85 941 [[Atomic mass unit|Dalton]].<ref>{{Cite web|url=https://www.uniprot.org/uniprot/Q14765|title=STAT4 - Signal transducer and activator of transcription 4 - Homo sapiens (Human) - STAT4 gene & protein|website=www.uniprot.org|access-date=2019-02-09}}</ref>


== Expression ==
== Expression ==
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Secreted by leukocytes, respectively fibroblasts, IFNα IFNβ together regulate antiviral immunity, cell proliferation and anti-tumor effects.<ref>{{cite journal | vauthors = Li SF, Gong MJ, Zhao FR, Shao JJ, Xie YL, Zhang YG, Chang HY | title = Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection | journal = Cellular Physiology and Biochemistry | volume = 51 | issue = 5 | pages = 2377–2396 | date = 2018 | pmid = 30537741 | doi = 10.1159/000495897 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Rönnblom L | title = The type I interferon system in the etiopathogenesis of autoimmune diseases | journal = Upsala Journal of Medical Sciences | volume = 116 | issue = 4 | pages = 227–37 | date = November 2011 | pmid = 22066971 | pmc = 3207297 | doi = 10.3109/03009734.2011.624649 }}</ref> During the initial phase of viral infection in NK cells, STAT1 activation is replaced by the activation of STAT4.
Secreted by leukocytes, respectively fibroblasts, IFNα IFNβ together regulate antiviral immunity, cell proliferation and anti-tumor effects.<ref>{{cite journal | vauthors = Li SF, Gong MJ, Zhao FR, Shao JJ, Xie YL, Zhang YG, Chang HY | title = Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection | journal = Cellular Physiology and Biochemistry | volume = 51 | issue = 5 | pages = 2377–2396 | date = 2018 | pmid = 30537741 | doi = 10.1159/000495897 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Rönnblom L | title = The type I interferon system in the etiopathogenesis of autoimmune diseases | journal = Upsala Journal of Medical Sciences | volume = 116 | issue = 4 | pages = 227–37 | date = November 2011 | pmid = 22066971 | pmc = 3207297 | doi = 10.3109/03009734.2011.624649 }}</ref> During the initial phase of viral infection in NK cells, STAT1 activation is replaced by the activation of STAT4.


=== Il-23 ===
=== 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 IL12β<sub>1</sub> and IL23R subunits, which upon binding of IL-23 promotes the phosphorylation STAT4. The presence of IL12β<sub>1</sub> 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.<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R | journal = Journal of Immunology | volume = 168 | issue = 11 | pages = 5699–708 | date = June 2002 | pmid = 12023369 | doi = 10.4049/jimmunol.168.11.5699 | doi-access = free }}</ref>
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 IL12β<sub>1</sub> and IL23R subunits, which upon binding of IL-23 promotes the phosphorylation STAT4. The presence of IL12β<sub>1</sub> 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.<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R | journal = Journal of Immunology | volume = 168 | issue = 11 | pages = 5699–708 | date = June 2002 | pmid = 12023369 | doi = 10.4049/jimmunol.168.11.5699 | doi-access = free }}</ref>
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== Inhibitors of STAT4 signalling pathways ==
== 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.<ref>{{cite journal | vauthors = Alexander WS | title = Suppressors of cytokine signalling (SOCS) in the immune system | journal = Nature Reviews. Immunology | volume = 2 | issue = 6 | pages = 410–6 | date = June 2002 | pmid = 12093007 | doi = 10.1038/nri818 | s2cid = 38009419 }}</ref>
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.<ref>{{cite journal | vauthors = Alexander WS | title = Suppressors of cytokine signalling (SOCS) in the immune system | journal = Nature Reviews. Immunology | volume = 2 | issue = 6 | pages = 410–6 | date = June 2002 | pmid = 12093007 | doi = 10.1038/nri818 | s2cid = 38009419 }}</ref>


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).<ref name=":0" />
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).<ref name=":0" />
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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 [[Ulcerative colitis|colitis ulcerative]]<ref>{{cite journal | vauthors = Ohtani K, Ohtsuka Y, Ikuse T, Baba Y, Yamakawa Y, Aoyagi Y, Fujii T, Kudo T, Nagata S, Shimizu T | display-authors = 6 | title = Increased mucosal expression of GATA-3 and STAT-4 in pediatric ulcerative colitis | journal = Pediatrics International | volume = 52 | issue = 4 | pages = 584–9 | date = August 2010 | pmid = 20030749 | doi = 10.1111/j.1442-200X.2009.03019.x | s2cid = 21910658 }}</ref> and skin T cells of [[Psoriasis|psoriatic]] patients.<ref>{{cite journal | vauthors = Eriksen KW, Lovato P, Skov L, Krejsgaard T, Kaltoft K, Geisler C, Ødum N | title = Increased sensitivity to interferon-alpha in psoriatic T cells | journal = The Journal of Investigative Dermatology | volume = 125 | issue = 5 | pages = 936–44 | date = November 2005 | pmid = 16297193 | doi = 10.1111/j.0022-202X.2005.23864.x | doi-access = free }}</ref> Moreover, STAT4 -/- mice developed less severe [[Experimental autoimmune encephalomyelitis|experimental autoimmune encephalo-myelitis]] (EAE) than the wild type mice.<ref>{{cite journal | vauthors = Chitnis T, Najafian N, Benou C, Salama AD, Grusby MJ, Sayegh MH, Khoury SJ | title = Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis | journal = The Journal of Clinical Investigation | volume = 108 | issue = 5 | pages = 739–47 | date = September 2001 | pmid = 11544280 | pmc = 209380 | doi = 10.1172/JCI12563 }}</ref><ref name="Korn_2009">{{cite journal | vauthors = Korn T, Bettelli E, Oukka M, Kuchroo VK | author4-link=Vijay Kuchroo | title = IL-17 and Th17 Cells | journal = Annual Review of Immunology | volume = 27 | issue = | pages = 485–517 | date = 2009 | pmid = 19132915 | doi = 10.1146/annurev.immunol.021908.132710 }}</ref>
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 [[Ulcerative colitis|colitis ulcerative]]<ref>{{cite journal | vauthors = Ohtani K, Ohtsuka Y, Ikuse T, Baba Y, Yamakawa Y, Aoyagi Y, Fujii T, Kudo T, Nagata S, Shimizu T | display-authors = 6 | title = Increased mucosal expression of GATA-3 and STAT-4 in pediatric ulcerative colitis | journal = Pediatrics International | volume = 52 | issue = 4 | pages = 584–9 | date = August 2010 | pmid = 20030749 | doi = 10.1111/j.1442-200X.2009.03019.x | s2cid = 21910658 }}</ref> and skin T cells of [[Psoriasis|psoriatic]] patients.<ref>{{cite journal | vauthors = Eriksen KW, Lovato P, Skov L, Krejsgaard T, Kaltoft K, Geisler C, Ødum N | title = Increased sensitivity to interferon-alpha in psoriatic T cells | journal = The Journal of Investigative Dermatology | volume = 125 | issue = 5 | pages = 936–44 | date = November 2005 | pmid = 16297193 | doi = 10.1111/j.0022-202X.2005.23864.x | doi-access = free }}</ref> Moreover, STAT4 -/- mice developed less severe [[Experimental autoimmune encephalomyelitis|experimental autoimmune encephalo-myelitis]] (EAE) than the wild type mice.<ref>{{cite journal | vauthors = Chitnis T, Najafian N, Benou C, Salama AD, Grusby MJ, Sayegh MH, Khoury SJ | title = Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis | journal = The Journal of Clinical Investigation | volume = 108 | issue = 5 | pages = 739–47 | date = September 2001 | pmid = 11544280 | pmc = 209380 | doi = 10.1172/JCI12563 }}</ref><ref name="Korn_2009">{{cite journal | vauthors = Korn T, Bettelli E, Oukka M, Kuchroo VK | author4-link=Vijay Kuchroo | title = IL-17 and Th17 Cells | journal = Annual Review of Immunology | volume = 27 | issue = | pages = 485–517 | date = 2009 | pmid = 19132915 | doi = 10.1146/annurev.immunol.021908.132710 }}</ref>


Intronic [[Gene polymorphism|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)<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus | journal = The New England Journal of Medicine | volume = 357 | issue = 10 | pages = 977–86 | date = September 2007 | pmid = 17804842 | pmc = 2630215 | doi = 10.1056/NEJMoa073003 }}</ref> and [[rheumatoid arthritis]]<ref>{{cite journal | vauthors = Liang YL, Wu H, Shen X, Li PQ, Yang XQ, Liang L, Tian WH, Zhang LF, Xie XD | display-authors = 6 | title = Association of STAT4 rs7574865 polymorphism with autoimmune diseases: a meta-analysis | journal = Molecular Biology Reports | volume = 39 | issue = 9 | pages = 8873–82 | date = September 2012 | pmid = 22714917 | doi = 10.1007/s11033-012-1754-1 | s2cid = 10984779 }}</ref> as well as [[Sjögren syndrome|Sjögren's disease]] (SD),<ref>{{cite journal | vauthors = Palomino-Morales RJ, Diaz-Gallo LM, Witte T, Anaya JM, Martín J | title = Influence of STAT4 polymorphism in primary Sjögren's syndrome | journal = The Journal of Rheumatology | volume = 37 | issue = 5 | pages = 1016–9 | date = May 2010 | pmid = 20360187 | doi = 10.3899/jrheum.091007 | s2cid = 40894904 }}</ref> [[Systemic scleroderma|systemic sclerosis]],<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype | journal = Human Molecular Genetics | volume = 18 | issue = 11 | pages = 2071–7 | date = June 2009 | pmid = 19286670 | doi = 10.1093/hmg/ddp119 | doi-access = free }}</ref> [[psoriasis]]<ref>{{cite journal | vauthors = Villarreal-Martínez A, Gallardo-Blanco H, Cerda-Flores R, Torres-Muñoz I, Gómez-Flores M, Salas-Alanís J, Ocampo-Candiani J, Martínez-Garza L | display-authors = 6 | title = Candidate gene polymorphisms and risk of psoriasis: A pilot study | journal = Experimental and Therapeutic Medicine | volume = 11 | issue = 4 | pages = 1217–1222 | date = April 2016 | pmid = 27073425 | pmc = 4812537 | doi = 10.3892/etm.2016.3066 }}</ref> and also [[Diabetes mellitus type 1|type-1 diabetes]].<ref>{{cite journal | vauthors = Santin I, Eizirik DL | title = Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and β-cell apoptosis | journal = Diabetes, Obesity & Metabolism | volume = 15 Suppl 3 | issue = s3 | pages = 71–81 | date = September 2013 | pmid = 24003923 | doi = 10.1111/dom.12162 | s2cid = 22297620 | doi-access = free }}</ref> High incident of STAT4 genetic polymorphisms and susceptibility to autoimmune diseases is a reason to consider the STAT4 as general autoimmune disease susceptibility locus.<ref>{{cite journal | vauthors = Korman BD, Kastner DL, Gregersen PK, Remmers EF | title = STAT4: genetics, mechanisms, and implications for autoimmunity | journal = Current Allergy and Asthma Reports | volume = 8 | issue = 5 | pages = 398–403 | date = September 2008 | pmid = 18682104 | pmc = 2562257 | doi = 10.1007/s11882-008-0077-8 }}</ref>
Intronic [[Gene polymorphism|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)<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus | journal = The New England Journal of Medicine | volume = 357 | issue = 10 | pages = 977–86 | date = September 2007 | pmid = 17804842 | pmc = 2630215 | doi = 10.1056/NEJMoa073003 }}</ref> and [[rheumatoid arthritis]]<ref>{{cite journal | vauthors = Liang YL, Wu H, Shen X, Li PQ, Yang XQ, Liang L, Tian WH, Zhang LF, Xie XD | display-authors = 6 | title = Association of STAT4 rs7574865 polymorphism with autoimmune diseases: a meta-analysis | journal = Molecular Biology Reports | volume = 39 | issue = 9 | pages = 8873–82 | date = September 2012 | pmid = 22714917 | doi = 10.1007/s11033-012-1754-1 | s2cid = 10984779 }}</ref> as well as [[Sjögren syndrome|Sjögren's disease]] (SD),<ref>{{cite journal | vauthors = Palomino-Morales RJ, Diaz-Gallo LM, Witte T, Anaya JM, Martín J | title = Influence of STAT4 polymorphism in primary Sjögren's syndrome | journal = The Journal of Rheumatology | volume = 37 | issue = 5 | pages = 1016–9 | date = May 2010 | pmid = 20360187 | doi = 10.3899/jrheum.091007 | s2cid = 40894904 | doi-access = free }}</ref> [[Systemic scleroderma|systemic sclerosis]],<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype | journal = Human Molecular Genetics | volume = 18 | issue = 11 | pages = 2071–7 | date = June 2009 | pmid = 19286670 | doi = 10.1093/hmg/ddp119 | doi-access = free }}</ref> [[psoriasis]]<ref>{{cite journal | vauthors = Villarreal-Martínez A, Gallardo-Blanco H, Cerda-Flores R, Torres-Muñoz I, Gómez-Flores M, Salas-Alanís J, Ocampo-Candiani J, Martínez-Garza L | display-authors = 6 | title = Candidate gene polymorphisms and risk of psoriasis: A pilot study | journal = Experimental and Therapeutic Medicine | volume = 11 | issue = 4 | pages = 1217–1222 | date = April 2016 | pmid = 27073425 | pmc = 4812537 | doi = 10.3892/etm.2016.3066 }}</ref> and also [[Diabetes mellitus type 1|type-1 diabetes]].<ref>{{cite journal | vauthors = Santin I, Eizirik DL | title = Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and β-cell apoptosis | journal = Diabetes, Obesity & Metabolism | volume = 15 Suppl 3 | issue = s3 | pages = 71–81 | date = September 2013 | pmid = 24003923 | doi = 10.1111/dom.12162 | s2cid = 22297620 | doi-access = free }}</ref> High incident of STAT4 genetic polymorphisms and susceptibility to autoimmune diseases is a reason to consider the STAT4 as general autoimmune disease susceptibility locus.<ref>{{cite journal | vauthors = Korman BD, Kastner DL, Gregersen PK, Remmers EF | title = STAT4: genetics, mechanisms, and implications for autoimmunity | journal = Current Allergy and Asthma Reports | volume = 8 | issue = 5 | pages = 398–403 | date = September 2008 | pmid = 18682104 | pmc = 2562257 | doi = 10.1007/s11882-008-0077-8 }}</ref>


== References ==
== References ==

Latest revision as of 07:46, 3 June 2024

STAT4
Identifiers
AliasesSTAT4, SLEB11, signal transducer and activator of transcription 4
External IDsOMIM: 600558; MGI: 103062; HomoloGene: 20679; GeneCards: STAT4; OMA:STAT4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6775

20849

Ensembl

ENSG00000138378

ENSMUSG00000062939

UniProt

Q14765

P42228

RefSeq (mRNA)

NM_001243835
NM_003151

NM_011487
NM_001308266

RefSeq (protein)

NP_001230764
NP_003142

NP_001295195
NP_035617

Location (UCSC)Chr 2: 191.03 – 191.15 MbChr 1: 52.03 – 52.15 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[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 of Janus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive CD4+ T cells[7] and IFN-γ production in response to IL-12.[8] There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma (IFN-γ )production downstream.[9]

Structure

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Human as well murine STAT4 genes lie next to STAT1 gene locus suggesting that the genes arose by gene duplication.[5] 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.[10][11] The length of the protein is 748 amino acids, and the molecular weight is 85 941 Dalton.[12]

Expression

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Distribution of STAT4 is restricted to myeloid cells, thymus and testis.[5] In resting human T cells it is expressed at very low levels, but its production is amplified by PHA stimulation.[8]

Cytokines activating STAT4

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IL-12

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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.[13]

IFNα and IFNβ

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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.

IL-23

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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.

Inhibitors of STAT4 signalling pathways

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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.[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]

Target genes

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STAT4 binds to hundreds of sites in the genome,[18] among others to the promoters of genes for cytokines (IFN-γ, TNF), receptors (IL18R1, IL12rβ2, IL18RAP), and signaling factors (MYD88).[18]

Disease

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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[19] and skin T cells of psoriatic patients.[20] Moreover, STAT4 -/- mice developed less severe experimental autoimmune encephalo-myelitis (EAE) than the wild type mice.[21][22]

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)[23] and rheumatoid arthritis[24] as well as Sjögren's disease (SD),[25] systemic sclerosis,[26] psoriasis[27] and also type-1 diabetes.[28] High incident of STAT4 genetic polymorphisms and susceptibility to autoimmune diseases is a reason to consider the STAT4 as general autoimmune disease susceptibility locus.[29]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000138378 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000062939 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c Yamamoto K, Quelle FW, Thierfelder WE, Kreider BL, Gilbert DJ, Jenkins NA, et al. (July 1994). "Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation". Molecular and Cellular Biology. 14 (7): 4342–9. doi:10.1128/mcb.14.7.4342. PMC 358805. PMID 8007943.
  6. ^ Darnell JE, Kerr IM, Stark GR (June 1994). "Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins". Science. 264 (5164): 1415–21. Bibcode:1994Sci...264.1415D. doi:10.1126/science.8197455. PMID 8197455.
  7. ^ Kaplan MH (2005). "STAT4: a critical regulator of inflammation in vivo". Immunologic Research. 31 (3): 231–42. doi:10.1385/IR:31:3:231. PMID 15888914.
  8. ^ a b Bacon CM, Petricoin EF, Ortaldo JR, Rees RC, Larner AC, Johnston JA, O'Shea JJ (August 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 (16): 7307–11. Bibcode:1995PNAS...92.7307B. doi:10.1073/pnas.92.16.7307. PMC 41328. PMID 7638186.
  9. ^ Hoey T, Zhang S, Schmidt N, Yu Q, Ramchandani S, Xu X, et al. (August 2003). "Distinct requirements for the naturally occurring splice forms Stat4alpha and Stat4beta in IL-12 responses". The EMBO Journal. 22 (16): 4237–48. doi:10.1093/emboj/cdg393. PMC 175783. PMID 12912921.
  10. ^ Chang HC, Zhang S, Oldham I, Naeger L, Hoey T, Kaplan MH (August 2003). "STAT4 requires the N-terminal domain for efficient phosphorylation". The Journal of Biological Chemistry. 278 (34): 32471–7. doi:10.1074/jbc.M302776200. PMID 12805384.
  11. ^ a b Yang C, Mai H, Peng J, Zhou B, Hou J, Jiang D (2020). "STAT4: an immunoregulator contributing to diverse human diseases". International Journal of Biological Sciences. 16 (9): 1575–1585. doi:10.7150/ijbs.41852. PMC 7097918. PMID 32226303.
  12. ^ "STAT4 - Signal transducer and activator of transcription 4 - Homo sapiens (Human) - STAT4 gene & protein". www.uniprot.org. Retrieved 2019-02-09.
  13. ^ Rapp M, Lau CM, Adams NM, Weizman OE, O'Sullivan TE, Geary CD, Sun JC (December 2017). "Core-binding factor β and Runx transcription factors promote adaptive natural killer cell responses". Science Immunology. 2 (18): eaan3796. doi:10.1126/sciimmunol.aan3796. PMC 6265048. PMID 29222089.
  14. ^ Li SF, Gong MJ, Zhao FR, Shao JJ, Xie YL, Zhang YG, Chang HY (2018). "Type I Interferons: Distinct Biological Activities and Current Applications for Viral Infection". Cellular Physiology and Biochemistry. 51 (5): 2377–2396. doi:10.1159/000495897. PMID 30537741.
  15. ^ Rönnblom L (November 2011). "The type I interferon system in the etiopathogenesis of autoimmune diseases". Upsala Journal of Medical Sciences. 116 (4): 227–37. doi:10.3109/03009734.2011.624649. PMC 3207297. PMID 22066971.
  16. ^ Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, et al. (June 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 (11): 5699–708. doi:10.4049/jimmunol.168.11.5699. PMID 12023369.
  17. ^ Alexander WS (June 2002). "Suppressors of cytokine signalling (SOCS) in the immune system". Nature Reviews. Immunology. 2 (6): 410–6. doi:10.1038/nri818. PMID 12093007. S2CID 38009419.
  18. ^ a b Good SR, Thieu VT, Mathur AN, Yu Q, Stritesky GL, Yeh N, et al. (September 2009). "Temporal induction pattern of STAT4 target genes defines potential for Th1 lineage-specific programming". Journal of Immunology. 183 (6): 3839–47. doi:10.4049/jimmunol.0901411. PMC 2748807. PMID 19710469.
  19. ^ 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. PMID 20030749. S2CID 21910658.
  20. ^ Eriksen KW, Lovato P, Skov L, Krejsgaard T, Kaltoft K, Geisler C, Ødum N (November 2005). "Increased sensitivity to interferon-alpha in psoriatic T cells". The Journal of Investigative Dermatology. 125 (5): 936–44. doi:10.1111/j.0022-202X.2005.23864.x. PMID 16297193.
  21. ^ Chitnis T, Najafian N, Benou C, Salama AD, Grusby MJ, Sayegh MH, Khoury SJ (September 2001). "Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis". The Journal of Clinical Investigation. 108 (5): 739–47. doi:10.1172/JCI12563. PMC 209380. PMID 11544280.
  22. ^ Korn T, Bettelli E, Oukka M, Kuchroo VK (2009). "IL-17 and Th17 Cells". Annual Review of Immunology. 27: 485–517. doi:10.1146/annurev.immunol.021908.132710. PMID 19132915.
  23. ^ Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, et al. (September 2007). "STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus". The New England Journal of Medicine. 357 (10): 977–86. doi:10.1056/NEJMoa073003. PMC 2630215. PMID 17804842.
  24. ^ 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. PMID 22714917. S2CID 10984779.
  25. ^ Palomino-Morales RJ, Diaz-Gallo LM, Witte T, Anaya JM, Martín J (May 2010). "Influence of STAT4 polymorphism in primary Sjögren's syndrome". The Journal of Rheumatology. 37 (5): 1016–9. doi:10.3899/jrheum.091007. PMID 20360187. S2CID 40894904.
  26. ^ Rueda B, Broen J, Simeon C, Hesselstrand R, Diaz B, Suárez H, et al. (June 2009). "The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype". Human Molecular Genetics. 18 (11): 2071–7. doi:10.1093/hmg/ddp119. PMID 19286670.
  27. ^ Villarreal-Martínez A, Gallardo-Blanco H, Cerda-Flores R, Torres-Muñoz I, Gómez-Flores M, Salas-Alanís J, et al. (April 2016). "Candidate gene polymorphisms and risk of psoriasis: A pilot study". Experimental and Therapeutic Medicine. 11 (4): 1217–1222. doi:10.3892/etm.2016.3066. PMC 4812537. PMID 27073425.
  28. ^ Santin I, Eizirik DL (September 2013). "Candidate genes for type 1 diabetes modulate pancreatic islet inflammation and β-cell apoptosis". Diabetes, Obesity & Metabolism. 15 Suppl 3 (s3): 71–81. doi:10.1111/dom.12162. PMID 24003923. S2CID 22297620.
  29. ^ Korman BD, Kastner DL, Gregersen PK, Remmers EF (September 2008). "STAT4: genetics, mechanisms, and implications for autoimmunity". Current Allergy and Asthma Reports. 8 (5): 398–403. doi:10.1007/s11882-008-0077-8. PMC 2562257. PMID 18682104.

Further reading

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