STAT4

Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family.[5] It is required for the development of Th1 cells from naive CD4+ T cells[6] and IFN-γ production in response to IL-12.[7]

STAT4
Identifiers
Aliases	STAT4, SLEB11, signal transducer and activator of transcription 4
External IDs	OMIM: 600558 MGI: 103062 HomoloGene: 20679 GeneCards: STAT4
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q32.2-q32.3 Start 191,029,576 bp[1] End 191,151,596 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1 C1.1|1 26.67 cM Start 51,987,148 bp[2] End 52,107,189 bp[2]
Gene ontology Molecular function • GO:0001948 protein binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • DNA binding • identical protein binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific Cellular component • cytoplasm • cell nucleus • nucleoplasm • cytosol Biological process • transcription, DNA-templated • regulation of transcription, DNA-templated • JAK-STAT cascade • signal transduction • positive regulation of transcription from RNA polymerase II promoter • interleukin-12-mediated signaling pathway • cytokine-mediated signaling pathway • interleukin-21-mediated signaling pathway • interleukin-23-mediated signaling pathway • interleukin-35-mediated signaling pathway • defense response • regulation of cell proliferation • response to peptide hormone Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
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 Mb	Chr 1: 51.99 – 52.11 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Structure

Human as well murine STAT4 genes lie next to STAT1 gene locus suggesting that the genes arose by gene duplication.[5] STAT proteins have several functional domains, including an N-terminal interaction domain, a central DNA-binding domain, an SH2 domain, and the C-terminal transactivation domain.[8] The length of the protein is 748 amino acids, and the molecular weight is 85 941 Dalton.[9]

Expression

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.[7]

Activation

Two chains of IL-12 receptor form heterodimer after IL-12 binding and activate the receptor associated JAK kinases, termed JAK2 and TYK2. Stat4 is phosphorylated by these tyrosine kinases, homodimerizes via its SH2 domain and translocates into nucleus to activate gene transcription.[10]

Target genes

STAT4 binds to hundreds of sites in the genome,[11] among others to the promoters of genes for cytokines (IFN-γ, TNF), receptors (IL18R1, IL12rβ2, IL18RAP), and signaling factors (MYD88).[11]

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[12] and skin T cells of psoriatic patients.[13] Moreover, STAT4 -/- mice developed less severe experimental autoimmune encephalo-myelitis (EAE) than the wild type mice.[14]

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)[15] and rheumatoid arthritis [16] as well as Sjögren's disease (SD),[17] systemic sclerosis,[18] psoriasis[19] and also type-1 diabetes.[20] High incident of STAT4 genetic polymorphisms and susceptibility to autoimmune diseases is a reason to consider the STAT4 as general autoimmune disease susceptibility locus.[21]

References

1. GRCh38: Ensembl release 89: ENSG00000138378 - Ensembl, May 2017
2. 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. Yamamoto K, Quelle FW, Thierfelder WE, Kreider BL, Gilbert DJ, Jenkins NA, Copeland NG, Silvennoinen O, Ihle JN (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. 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.
7. 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.
8. 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.
9. "STAT4 - Signal transducer and activator of transcription 4 - Homo sapiens (Human) - STAT4 gene & protein". www.uniprot.org. Retrieved 2019-02-09.
10. Wurster AL, Tanaka T, Grusby MJ (May 2000). "The biology of Stat4 and Stat6". Oncogene. 19 (21): 2577–84. doi:10.1038/sj.onc.1203485. PMID 10851056.
11. Good SR, Thieu VT, Mathur AN, Yu Q, Stritesky GL, Yeh N, O'Malley JT, Perumal NB, Kaplan MH (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.
12. Ohtani, Kiyotaka; Ohtsuka, Yoshikazu; Ikuse, Tamaki; Baba, Yosuke; Yamakawa, Yoko; Aoyagi, Yo; Fujii, Tohru; Kudo, Takahiro; Nagata, Satoru (2010). "Increased mucosal expression of GATA-3 and STAT-4 in pediatric ulcerative colitis". Pediatrics International. 52 (4): 584–589. doi:10.1111/j.1442-200X.2009.03019.x. ISSN 1442-200X. PMID 20030749. S2CID 21910658.
13. Eriksen, Karsten Wessel; Lovato, Paola; Skov, Lone; Krejsgaard, Thorbjørn; Kaltoft, Keld; Geisler, Carsten; Ødum, Niels (November 2005). "Increased sensitivity to interferon-alpha in psoriatic T cells". The Journal of Investigative Dermatology. 125 (5): 936–944. doi:10.1111/j.0022-202X.2005.23864.x. ISSN 0022-202X. PMID 16297193.
14. Khoury, Samia J.; Sayegh, Mohamed H.; Grusby, Michael J.; Salama, Alan D.; Benou, Christina; Najafian, Nader; Chitnis, Tanuja (2001-09-01). "Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis". The Journal of Clinical Investigation. 108 (5): 739–747. doi:10.1172/JCI12563. ISSN 0021-9738. PMC 209380. PMID 11544280.
15. 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 (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.
16. Liang YL, Wu H, Shen X, Li PQ, Yang XQ, Liang L, Tian WH, Zhang LF, Xie XD (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.
17. 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.
18. 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.
19. Villarreal-Martínez A, Gallardo-Blanco H, Cerda-Flores R, Torres-Muñoz I, Gómez-Flores M, Salas-Alanís J, Ocampo-Candiani J, Martínez-Garza L (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.
20. 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.
21. 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

• Svenungsson E, Gustafsson J, Leonard D, Sandling J, Gunnarsson I, Nordmark G, Jönsen A, Bengtsson AA, Sturfelt G, Rantapää-Dahlqvist S, Elvin K, Sundin U, Garnier S, Simard JF, Sigurdsson S, Padyukov L, Syvänen AC, Rönnblom L (May 2010). "A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus". Annals of the Rheumatic Diseases. 69 (5): 834–40. doi:10.1136/ard.2009.115535. hdl:10616/40867. PMID 19762360. S2CID 23362449.

External links

• STAT4+Transcription+Factor at the US National Library of Medicine Medical Subject Headings (MeSH)