STAT6 explained

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.^[1] 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.

Molecular biology

In the human genome, STAT6 protein is encoded by the STAT6 gene, located on the chromosome 12q13.3-q14.1.^[2] The gene encompasses over 19 kb and consists of 23 exons.^[3] STAT6 shares structural similarity with the other STAT proteins and is composed of the N-terminal domain, DNA binding domain, SH3- like domain, SH2 domain and transactivation domain (TAD).

STAT proteins are activated by the Janus family (JAKs) tyrosine kinases in response to cytokine exposure.^[4] STAT6 is activated by cytokines interleukin-4 (IL-4), and interleukin-13 (IL-13) with their receptors that both contain the α subunit of the IL-4 receptor (IL-4Rα). Tyrosine phosporylation of STAT6 after stimulation by IL-4 results in the formation of STAT6 homodimers that bind specific DNA elements via a DNA-binding domain.^[5]

Function

STAT6-mediated signaling pathway is required for the development of T-helper type 2 (Th2) cells and Th2 immune response. Expression of Th2 cytokines, including IL-4, IL-13, and IL-5, was reduced in STAT6-deficient mice. STAT 6 protein is crucial in IL4 mediated biological responses. It was found that STAT6 induce the expression of BCL2L1/BCL-X(L), which is responsible for the anti-apoptotic activity of IL4. IL-4 stimulates the phosphorylation of IL-4 receptor, which recruits cytosolic STAT6 by its SH2 domain and STAT6 is phosphorylated on tyrosine 641 (Y641) by JAK1, which results in the dimerization and nuclear translocation of STAT6 to activate target genes.^[6] Knockout studies in mice suggested the roles of this gene in differentiation of T helper 2 (Th2), expression of cell surface markers, and class switch of immunoglobulins.^[7]

Activation of STAT6 signaling pathway is necessary in macrophage function, and is required for the M2 subtype activation of macrophages.^{[8] [9] [10]} STAT6 protein also regulates other transcription factor as Gata3, which is important regulator of Th2 differentiation. STAT6 is also required for the development of IL-9-secreting T cells.

STAT6 also plays a critical role in Th2 lung inflammatory responses including clearance of parasitic infections and in the pathogenesis of asthma. Th2-cell derived cytokines as IL-4 and IL-13 induce the production of IgE which is  a major mediator in allergic response. Association studies searching for relation of polymorphisms in STAT6 with IgE level or asthma discovered a few polymorphisms significantly associated with examined traits. Only two polymorphisms showed repeatedly significant clinical association and/or functional effect on STAT6 function (GT repeats in exon 1 and rs324011 polymorphism in intron 2).

Interactions

STAT6 has been shown to interact with:

• CREB-binding protein,^[11]
• EP300,^[12]
• IRF4,^[13]
• NFKB1,^[14]
• Nuclear receptor coactivator 1,^{[11] [15]} and
• SND1.^[16]

Pathology

• Gene fusion
  • Recurrent somatic fusions of the two genes, NGFI-A–binding protein 2 (NAB2) and STAT6, located at chromosomal region 12q13, have been identified in solitary fibrous tumors.^[17]
• Amplification
  • STAT6 is amplified in a subset of dedifferentiated liposarcoma.^[18]

See also

• Interleukin 4

References

1. Goenka S, Kaplan MH . Transcriptional regulation by STAT6 . Immunologic Research . 50 . 1 . 87–96 . May 2011 . 21442426 . 3107597 . 10.1007/s12026-011-8205-2 .
2. Patel BK, Keck CL, O'Leary RS, Popescu NC, LaRochelle WJ . Localization of the human stat6 gene to chromosome 12q13.3-q14.1, a region implicated in multiple solid tumors . Genomics . 52 . 2 . 192–200 . September 1998 . 9782085 . 10.1006/geno.1998.5436 .
3. Godava M, Vrtel R, Vodicka R . STAT6 - polymorphisms, haplotypes and epistasis in relation to atopy and asthma . Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia . 157 . 2 . 172–80 . June 2013 . 23752766 . 10.5507/bp.2013.043 . free .
4. Walford HH, Doherty TA . STAT6 and lung inflammation . JAK-STAT . 2 . 4 . e25301 . October 2013 . 24416647 . 3876430 . 10.4161/jkst.25301 .
5. Leek JP, Hamlin PJ, Bell SM, Lench NJ . Assignment of the STAT6 gene (STAT6) to human chromosome band 12q13 by in situ hybridization . Cytogenetics and Cell Genetics . 79 . 3–4 . 208–9 . 1997 . 9605853 . 10.1159/000134723 .
6. Chen H, Sun H, You F, Sun W, Zhou X, Chen L, Yang J, Wang Y, Tang H, Guan Y, Xia W, Gu J, Ishikawa H, Gutman D, Barber G, Qin Z, Jiang Z . Activation of STAT6 by STING is critical for antiviral innate immunity . Cell . 147 . 2 . 436–46 . October 2011 . 22000020 . 10.1016/j.cell.2011.09.022 . free .
7. Web site: STAT6 signal transducer and activator of transcription 6 [Homo sapiens (human)] - Gene - NCBI]. 2021-05-01. www.ncbi.nlm.nih.gov.
8. Binnemars-Postma K, Bansal R, Storm G, Prakash J . Targeting the Stat6 pathway in tumor-associated macrophages reduces tumor growth and metastatic niche formation in breast cancer . FASEB Journal . 32 . 2 . 969–978 . February 2018 . 29066614 . 10.1096/fj.201700629R . 3342014 . free .
9. Gong M, Zhuo X, Ma A . STAT6 Upregulation Promotes M2 Macrophage Polarization to Suppress Atherosclerosis . Medical Science Monitor Basic Research . 23 . 240–249 . June 2017 . 28615615 . 5484610 . 10.12659/msmbr.904014 .
10. Book: Waqas SF, Ampem G, Röszer T . Nuclear Receptors . Analysis of IL-4/STAT6 Signaling in Macrophages . Methods in Molecular Biology . 1966 . 211–224 . 2019 . 31041750 . 10.1007/978-1-4939-9195-2_17 . 978-1-4939-9194-5 . 141465649 .
11. Litterst CM, Pfitzner E . Transcriptional activation by STAT6 requires the direct interaction with NCoA-1 . The Journal of Biological Chemistry . 276 . 49 . 45713–21 . December 2001 . 11574547 . 10.1074/jbc.M108132200 . free .
12. McDonald C, Reich NC . Cooperation of the transcriptional coactivators CBP and p300 with Stat6 . Journal of Interferon & Cytokine Research . 19 . 7 . 711–22 . July 1999 . 10454341 . 10.1089/107999099313550 .
13. Gupta S, Jiang M, Anthony A, Pernis AB . Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4 . The Journal of Experimental Medicine . 190 . 12 . 1837–48 . December 1999 . 10601358 . 2195723 . 10.1084/jem.190.12.1837 .
14. Shen CH, Stavnezer J . Interaction of stat6 and NF-kappaB: direct association and synergistic activation of interleukin-4-induced transcription . Molecular and Cellular Biology . 18 . 6 . 3395–404 . June 1998 . 9584180 . 108921 . 10.1128/mcb.18.6.3395 .
15. Litterst CM, Pfitzner E . An LXXLL motif in the transactivation domain of STAT6 mediates recruitment of NCoA-1/SRC-1 . The Journal of Biological Chemistry . 277 . 39 . 36052–60 . September 2002 . 12138096 . 10.1074/jbc.M203556200 . free .
16. Yang J, Aittomäki S, Pesu M, Carter K, Saarinen J, Kalkkinen N, Kieff E, Silvennoinen O . Identification of p100 as a coactivator for STAT6 that bridges STAT6 with RNA polymerase II . The EMBO Journal . 21 . 18 . 4950–8 . September 2002 . 12234934 . 126276 . 10.1093/emboj/cdf463 .
17. Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S . Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer . Journal of Clinical Oncology . 23 . 16 . 3706–12 . June 2005 . 15867200 . 10.1200/JCO.2005.00.232 . free .
18. Doyle LA, Tao D, Mariño-Enríquez A . STAT6 is amplified in a subset of dedifferentiated liposarcoma . Modern Pathology . 27 . 9 . 1231–7 . September 2014 . 24457460 . 10.1038/modpathol.2013.247 . free .

Further reading

• Jiang H, Harris MB, Rothman P . IL-4/IL-13 signaling beyond JAK/STAT . The Journal of Allergy and Clinical Immunology . 105 . 6 Pt 1 . 1063–70 . June 2000 . 10856136 . 10.1067/mai.2000.107604 . free .
• Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW . Signaling through the JAK/STAT pathway, recent advances and future challenges . Gene . 285 . 1–2 . 1–24 . February 2002 . 12039028 . 10.1016/S0378-1119(02)00398-0 .
• Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL . An interleukin-4-induced transcription factor: IL-4 Stat . Science . 265 . 5179 . 1701–6 . September 1994 . 8085155 . 10.1126/science.8085155 . 1994Sci...265.1701H .
• Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, Nakanishi K, Yoshida N, Kishimoto T, Akira S . Essential role of Stat6 in IL-4 signalling . Nature . 380 . 6575 . 627–30 . April 1996 . 8602263 . 10.1038/380627a0 . 4340375 . 1996Natur.380..627T .
• Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, Chu C, Quelle FW, Nosaka T, Vignali DA, Doherty PC, Grosveld G, Paul WE, Ihle JN . Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene . Nature . 380 . 6575 . 630–3 . April 1996 . 8602264 . 10.1038/380630a0 . 4334441 . 1996Natur.380..630S .
• Kotanides H, Reich NC . Interleukin-4-induced STAT6 recognizes and activates a target site in the promoter of the interleukin-4 receptor gene . The Journal of Biological Chemistry . 271 . 41 . 25555–61 . October 1996 . 8810328 . 10.1074/jbc.271.41.25555 . free .
• Mikita T, Campbell D, Wu P, Williamson K, Schindler U . Requirements for interleukin-4-induced gene expression and functional characterization of Stat6 . Molecular and Cellular Biology . 16 . 10 . 5811–20 . October 1996 . 8816495 . 231582 . 10.1128/mcb.16.10.5811 .
• Shen CH, Stavnezer J . Interaction of stat6 and NF-kappaB: direct association and synergistic activation of interleukin-4-induced transcription . Molecular and Cellular Biology . 18 . 6 . 3395–404 . June 1998 . 9584180 . 108921 . 10.1128/mcb.18.6.3395 .
• Leek JP, Hamlin PJ, Bell SM, Lench NJ . Assignment of the STAT6 gene (STAT6) to human chromosome band 12q13 by in situ hybridization . Cytogenetics and Cell Genetics . 79 . 3–4 . 208–9 . 1998 . 9605853 . 10.1159/000134723 .
• Mikita T, Kurama M, Schindler U . Synergistic activation of the germline epsilon promoter mediated by Stat6 and C/EBP beta . Journal of Immunology . 161 . 4 . 1822–8 . August 1998 . 10.4049/jimmunol.161.4.1822 . 9712049 . 82211469 . free .
• Patel BK, Keck CL, O'Leary RS, Popescu NC, LaRochelle WJ . Localization of the human stat6 gene to chromosome 12q13.3-q14.1, a region implicated in multiple solid tumors . Genomics . 52 . 2 . 192–200 . September 1998 . 9782085 . 10.1006/geno.1998.5436 .
• Zhu M, John S, Berg M, Leonard WJ . Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated signaling . Cell . 96 . 1 . 121–30 . January 1999 . 9989503 . 10.1016/S0092-8674(00)80965-4 . 14758136 . free .
• McDonald C, Reich NC . Cooperation of the transcriptional coactivators CBP and p300 with Stat6 . Journal of Interferon & Cytokine Research . 19 . 7 . 711–22 . July 1999 . 10454341 . 10.1089/107999099313550 .
• Harris MB, Chang CC, Berton MT, Danial NN, Zhang J, Kuehner D, Ye BH, Kvatyuk M, Pandolfi PP, Cattoretti G, Dalla-Favera R, Rothman PB . Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iepsilon transcription and immunoglobulin E switching . Molecular and Cellular Biology . 19 . 10 . 7264–75 . October 1999 . 10490661 . 84719 . 10.1128/mcb.19.10.7264 .
• Gupta S, Jiang M, Pernis AB . IFN-alpha activates Stat6 and leads to the formation of Stat2:Stat6 complexes in B cells . Journal of Immunology . 163 . 7 . 3834–41 . October 1999 . 10.4049/jimmunol.163.7.3834 . 10490982 . 255676952 . free .
• Gupta S, Jiang M, Anthony A, Pernis AB . Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4 . The Journal of Experimental Medicine . 190 . 12 . 1837–48 . December 1999 . 10601358 . 2195723 . 10.1084/jem.190.12.1837 .
• Daniel C, Salvekar A, Schindler U . A gain-of-function mutation in STAT6 . The Journal of Biological Chemistry . 275 . 19 . 14255–9 . May 2000 . 10747856 . 10.1074/jbc.C000129200 . free .
• Arinobu Y, Sugimoto R, Akaiwa M, Arima K, Otsuka T, Hamasaki N, Izuhara K . Augmentation of signal transducer and activation of transcription (STAT)6 and STAT3 expression in stimulated B and T cells . Biochemical and Biophysical Research Communications . 277 . 2 . 317–24 . October 2000 . 11032724 . 10.1006/bbrc.2000.3674 .
• Masuda A, Matsuguchi T, Yamaki K, Hayakawa T, Yoshikai Y . Interleukin-15 prevents mouse mast cell apoptosis through STAT6-mediated Bcl-xL expression . The Journal of Biological Chemistry . 276 . 28 . 26107–13 . July 2001 . 11369758 . 10.1074/jbc.M011475200 . free.