STAT4

Last updated
STAT4
Identifiers
Aliases STAT4 , SLEB11, signal transducer and activator of transcription 4
External IDs OMIM: 600558 MGI: 103062 HomoloGene: 20679 GeneCards: STAT4
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 Mb Chr 1: 52.03 – 52.15 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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, 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]

Contents

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 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

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

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. [13]

IFNα and IFNβ

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

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

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

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

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]

Related Research Articles

<span class="mw-page-title-main">Interferon</span> Signaling proteins released by host cells in response to the presence of pathogens

Interferons are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten their anti-viral defenses.

Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2, but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of beginnings, endings and duality, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first.

The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.

<span class="mw-page-title-main">Interleukin 12</span> Interleukin

Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the family of interleukin-12. IL-12 family is unique in comprising the only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35. Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.

<span class="mw-page-title-main">STAT protein</span> Family of intracellular transcription factors

Members of the signal transducer and activator of transcription (STAT) protein family are intracellular transcription factors that mediate many aspects of cellular immunity, proliferation, apoptosis and differentiation. They are primarily activated by membrane receptor-associated Janus kinases (JAK). Dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis which enhances the survival of tumors and immunosuppression. Gene knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.

<span class="mw-page-title-main">Interferon gamma</span> InterPro Family

Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed IFN-γ release assay used to test for tuberculosis. In humans, the IFN-γ protein is encoded by the IFNG gene.

<span class="mw-page-title-main">IL-2 receptor</span> Lymphocyte receptor specific for Interleukin-2

The interleukin-2 receptor (IL-2R) is a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called IL-2.

Type II cytokine receptors, also commonly known as class II cytokine receptors, are transmembrane proteins that are expressed on the surface of certain cells. They bind and respond to a select group of cytokines including interferon type I, interferon type II, interferon type III. and members of the interleukin-10 family These receptors are characterized by the lack of a WSXWS motif which differentiates them from type I cytokine receptors.

<span class="mw-page-title-main">Interferon-alpha/beta receptor</span> Heterodimeric receptor

The interferon-α/β receptor (IFNAR) is a virtually ubiquitous membrane receptor which binds endogenous type I interferon (IFN) cytokines. Endogenous human type I IFNs include many subtypes, such as interferons-α, -β, -ε, -κ, -ω, and -ζ.

<span class="mw-page-title-main">Interferon-gamma receptor</span> Mammalian protein found in Homo sapiens

The interferon-gamma receptor (IFNGR) protein complex is the heterodimer of two chains: IFNGR1 and IFNGR2. It binds interferon-γ, the sole member of interferon type II.

<span class="mw-page-title-main">STAT1</span> Transcription factor and coding gene in humans

Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the STAT1 gene. It is a member of the STAT protein family.

<span class="mw-page-title-main">Tyrosine kinase 2</span> Enzyme and coding gene in humans

Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.

<span class="mw-page-title-main">Janus kinase 3</span> Mammalian protein found in Homo sapiens

Tyrosine-protein kinase JAK3 is a tyrosine kinase enzyme that in humans is encoded by the JAK3 gene.

<span class="mw-page-title-main">Janus kinase 1</span>

JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family, the IL-4 receptor family, the gp130 receptor family. It is also important for transducing a signal by type I (IFN-α/β) and type II (IFN-γ) interferons, and members of the IL-10 family via type II cytokine receptors. Jak1 plays a critical role in initiating responses to multiple major cytokine receptor families. Loss of Jak1 is lethal in neonatal mice, possibly due to difficulties suckling. Expression of JAK1 in cancer cells enables individual cells to contract, potentially allowing them to escape their tumor and metastasize to other parts of the body.

<span class="mw-page-title-main">STAT6</span> Protein and coding gene in humans

Signal transducer and activator of transcription 6 (STAT6) is a transcription factor that belongs to the Signal Transducer and Activator of Transcription (STAT) family of proteins. The proteins of STAT family transmit signals from a receptor complex to the nucleus and activate gene expression. Similarly as other STAT family proteins, STAT6 is also activated by growth factors and cytokines. STAT6 is mainly activated by cytokines interleukin-4 and interleukin-13.

<span class="mw-page-title-main">Interferon alpha-1</span> Protein-coding gene in the species Homo sapiens

Interferon alpha-1 is a protein that in humans is encoded by the IFNA1 gene.

<span class="mw-page-title-main">IFNA2</span> Mammalian protein found in Homo sapiens

Interferon alpha-2 is a protein that in humans is encoded by the IFNA2 gene.

<span class="mw-page-title-main">IRF5</span> Protein-coding gene in the species Homo sapiens

Interferon regulatory factor 5 is a protein that in humans is encoded by the IRF5 gene. The IRF family is a group of transcription factors that are involved in signaling for virus responses in mammals along with regulation of certain cellular functions.

Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.

The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic domain called the Toll/Interleukin-1 (TIR) domain. The elicitation of different TLRs/IL-1Rs results in similar signaling cascades due to their homologous TIR motif leading to the activation of mitogen-activated protein kinases (MAPKs) and the IκB kinase (IKK) complex, which initiates a nuclear factor-κB (NF-κB) and AP-1-dependent transcriptional response of pro-inflammatory genes. Understanding the key players and their roles in the TLR/IL-1R pathway is important because the presence of mutations causing the abnormal regulation of Toll/IL-1R signaling leading to a variety of acute inflammatory and autoimmune diseases.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000138378 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 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. 1 2 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. 1 2 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. 1 2 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.

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