STAT2
Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the STAT2 gene.[5][6] It is a member of the STAT protein family. This protein is critical to the biological response of type I interferons (IFNs).[7] It functions as a transcription factor downstream of type I interferons. STAT2 sequence identity between mouse and human is only 68%.[8]
Function
[edit]The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. In response to IFN, this protein forms a complex with STAT1 and IFN regulatory factor family protein p48 (IRF9) and form ISGF-3 (IFN-stimulated gene factor-3), in which this protein acts as a transactivator, but lacks the ability to bind DNA directly.[9] The protein mediates innate antiviral activity. Mutations in this gene result in Immunodeficiency 44.[10] ISGF-3 proceeds the activation of genes via the IFN-stimulated response element (ISRE). ISRE-driven genes include Ly-6C, the double-stranded RNA kinase (PKR), 2´ to 5´ oligoadenylate synthase (OAS), MX and potentially MHC class I.[11] Transcription adaptor P300/CBP (EP300/CREBBP) has been shown to interact specifically with this protein, which is thought to be involved in the process of blocking IFN-alpha response by adenovirus.[6]
STAT2 knockout mice are unresponsive to type I IFN and extremely vulnerable to viral infection. They indicate the loss of the type I IFN autocrine loop and several defects in macrophages and T cell responses. Stat2-/- cells show differences in the biological response to IFN-α.[7]
Interactions
[edit]STAT2 has been shown to interact with:
STAT2 deficiency
[edit]Knockout mice
[edit]In double knockout STAT2 mice, an increased proliferation of M1, M2, and M1/M2 coexpressing macrophages during influenza-bacterial super-infection is observed. The bacterial clearance was also impaired by neutralization of IFN-γ (M1) and Arginase-1 (M2) what suggests that pulmonary macrophages expressing a mixed M1/M2 phenotype promote bacterial control during influenza-bacterial super-infection. Therefore the STAT2 signaling is associated with suppressing macrophage activation and bacterial control during influenza-bacterial super-infection.[24] These mice demonstrate no developmental defects. The knockout STAT2 and double knockout STAT mice in Vesicular stromatitis Indiana virus (VSV) model produce at least 10 times more virus plaque-forming units than the wild type (WT).[25] IFN-α pretreatment supplied protection in WT and STAT2+/- cells but not in double knockout STAT2 cells. IFN-γ pretreatment did not provide any antiviral response during infection of VSV.[26] This finding could be explained by the reduced level of STAT1 in cells of STAT2 knockout mice.[7] Additionally, the double knockout STAT2 mice are more sensitive to mouse cytomegalovirus (MCMV), severe fever thrombocytopenia syndrome virus, influenza virus, dengue virus (DNV) and Zika virus than control mice, which suggests that STAT2 plays a critical role in the suppression of virus replication in mice.[27][28][29][30]
Human autosomal recessive (AR) STAT2 deficiency
[edit]AR STAT2 deficiency was first time observed in 2 siblings. After routine immunization with measles-mump-rubella, one sibling developed disseminated vaccine-strain measles (MMR) but recovered and second sibling died in infancy from a viral infection due to primary immunodeficiency disorder. Later, the results showed that siblings were homozygous for absent expression of gene for STAT2. Patients with AR STAT2 deficiency have mutations which bring substitutions at important splice sites what leads to defected splicing and premature stop codons leading to a loss of expression of an interferon-stimulated gene. The typical clinical phenotype is disseminated infection after immunization with the live attenuated MMR vaccine. Some patients had also an onset of severe disease in infancy like infection with RSV, norovirus, coxsackievirus, adenovirus or enterovirus. One of the patients had CNS disease after the primary infection with EBV. EBV suppression was delayed in peripheral blood and cerebrospinal fluid as type I interferon signalling plays important role in the initial immune response against EBV.[31] During next 3 years, PCR test showed persistent EBV presence in blood as well as in cerebrospinal fluid despite anti-EBV IgG. CMV and VZV infections were severe as well in few patients. The virus infection was treated by high-dose of intravenous immunoglobulin (IVIG) after which patients recovered and became afebrile within 24 hours. IVIG has anti-inflammatory effect and suggests that the passive immunization could help to control the ongoing viral infections. Therefore, the monthly IgG therapy could be beneficial for patients with STAT2 deficiency during childhood, until their adaptive immune system has sufficiently developed. From the age 5 years, the frequency and severity of viral infections decreased and the age of 10 years the patients were mostly off all medication. In general, the patients with STAT2 deficiency are relatively healthy with no specific defects in their adaptive immunity or developmental abnormalities. These findings show that type I IFN signaling trough ISGF3 is not essential for host defense against the majority of common childhood viral pathogens. Despite a profoundly defective innate IFN response and evident susceptibility to some viral infections, STAT2-deficient individuals can live a relatively healthy life.[32]
It was also reported a homozygous STAT2 missense mutation (R148W/Q) which results to a STAT2 gain of function underlying fatal early-onset autoinflammation in three patients. This mutation leads to a persistent type I IFN response due to defective binding of the mutated STAT2 to ubiquitin specific peptidase 1 (USP18) which is an essential in the negative autofeedback loop where USP18 sterically hinders the binding of JAK1 to IFNAR1.[33][34] Therefore complete AR STAT2 deficiency usually causes disseminated LAV infection and recurrent natural viral infections. Penetrance is not complete for several viral infections and for complicated live measles vaccine disease.[35] These observation suggest that the phenotype of AR STAT2 deficiency could range from asymptomatic (the healthy adult) to fatal (childhood death from a crushing viral disease). The phenotype is less severe than human complete AR STAT1 deficiency but more severe than IFNAR1 or IFNAR2 deficiency. The human phenotype is less severe than in mice.
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000170581 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040033 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Yan R, Qureshi S, Zhong Z, Wen Z, Darnell JE (February 1995). "The genomic structure of the STAT genes: multiple exons in coincident sites in Stat1 and Stat2". Nucleic Acids Research. 23 (3): 459–63. doi:10.1093/nar/23.3.459. PMC 306697. PMID 7885841.
- ^ a b "Entrez Gene: STAT2 signal transducer and activator of transcription 2, 113kDa".
- ^ a b c Park C, Li S, Cha E, Schindler C (December 2000). "Immune response in Stat2 knockout mice". Immunity. 13 (6): 795–804. doi:10.1016/S1074-7613(00)00077-7. PMID 11163195.
- ^ Park C, Lecomte MJ, Schindler C (November 1999). "Murine Stat2 is uncharacteristically divergent". Nucleic Acids Research. 27 (21): 4191–9. doi:10.1093/nar/27.21.4191. PMC 148693. PMID 10518610.
- ^ Schindler C, Strehlow I (1999). Cytokines and STAT Signaling. Advances in Pharmacology. Vol. 47. pp. 113–74. doi:10.1016/s1054-3589(08)60111-8. ISBN 9780120329489. PMID 10582086.
- ^ https://www.genecards.org/cgi-bin/carddisp.pl?gene=STAT2&keywords=STAT2.
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- ^ Bhattacharya S, Eckner R, Grossman S, Oldread E, Arany Z, D'Andrea A, Livingston DM (September 1996). "Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha". Nature. 383 (6598): 344–7. Bibcode:1996Natur.383..344B. doi:10.1038/383344a0. PMID 8848048. S2CID 4306588.
- ^ a b Li X, Leung S, Kerr IM, Stark GR (April 1997). "Functional subdomains of STAT2 required for preassociation with the alpha interferon receptor and for signaling". Molecular and Cellular Biology. 17 (4): 2048–56. doi:10.1128/mcb.17.4.2048. PMC 232052. PMID 9121453.
- ^ Uddin S, Chamdin A, Platanias LC (October 1995). "Interaction of the transcriptional activator Stat-2 with the type I interferon receptor". The Journal of Biological Chemistry. 270 (42): 24627–30. doi:10.1074/jbc.270.42.24627. PMID 7559568.
- ^ Yan H, Krishnan K, Greenlund AC, Gupta S, Lim JT, Schreiber RD, et al. (March 1996). "Phosphorylated interferon-alpha receptor 1 subunit (IFNaR1) acts as a docking site for the latent form of the 113 kDa STAT2 protein". The EMBO Journal. 15 (5): 1064–74. doi:10.1002/j.1460-2075.1996.tb00444.x. PMC 450004. PMID 8605876.
- ^ Nguyen VP, Saleh AZ, Arch AE, Yan H, Piazza F, Kim J, Krolewski JJ (March 2002). "Stat2 binding to the interferon-alpha receptor 2 subunit is not required for interferon-alpha signaling". The Journal of Biological Chemistry. 277 (12): 9713–21. doi:10.1074/jbc.M111161200. PMID 11786546.
- ^ Horvath CM, Stark GR, Kerr IM, Darnell JE (December 1996). "Interactions between STAT and non-STAT proteins in the interferon-stimulated gene factor 3 transcription complex". Molecular and Cellular Biology. 16 (12): 6957–64. doi:10.1128/mcb.16.12.6957. PMC 231699. PMID 8943351.
- ^ Martinez-Moczygemba M, Gutch MJ, French DL, Reich NC (August 1997). "Distinct STAT structure promotes interaction of STAT2 with the p48 subunit of the interferon-alpha-stimulated transcription factor ISGF3". The Journal of Biological Chemistry. 272 (32): 20070–6. doi:10.1074/jbc.272.32.20070. PMID 9242679.
- ^ Lau JF, Nusinzon I, Burakov D, Freedman LP, Horvath CM (January 2003). "Role of metazoan mediator proteins in interferon-responsive transcription". Molecular and Cellular Biology. 23 (2): 620–8. doi:10.1128/mcb.23.2.620-628.2003. PMC 151539. PMID 12509459.
- ^ Huang M, Qian F, Hu Y, Ang C, Li Z, Wen Z (October 2002). "Chromatin-remodelling factor BRG1 selectively activates a subset of interferon-alpha-inducible genes". Nature Cell Biology. 4 (10): 774–81. doi:10.1038/ncb855. PMID 12244326. S2CID 251794.
- ^ Li X, Leung S, Qureshi S, Darnell JE, Stark GR (March 1996). "Formation of STAT1-STAT2 heterodimers and their role in the activation of IRF-1 gene transcription by interferon-alpha". The Journal of Biological Chemistry. 271 (10): 5790–4. doi:10.1074/jbc.271.10.5790. PMID 8621447.
- ^ Dumler I, Kopmann A, Wagner K, Mayboroda OA, Jerke U, Dietz R, et al. (August 1999). "Urokinase induces activation and formation of Stat4 and Stat1-Stat2 complexes in human vascular smooth muscle cells". The Journal of Biological Chemistry. 274 (34): 24059–65. doi:10.1074/jbc.274.34.24059. PMID 10446176.
- ^ Fagerlund R, Mélen K, Kinnunen L, Julkunen I (August 2002). "Arginine/lysine-rich nuclear localization signals mediate interactions between dimeric STATs and importin alpha 5". The Journal of Biological Chemistry. 277 (33): 30072–8. doi:10.1074/jbc.M202943200. PMID 12048190.
- ^ Gopal R, Lee B, McHugh KJ, Rich HE, Ramanan K, Mandalapu S, et al. (2018-09-25). "STAT2 Signaling Regulates Macrophage Phenotype During Influenza and Bacterial Super-Infection". Frontiers in Immunology. 9: 2151. doi:10.3389/fimmu.2018.02151. PMC 6178135. PMID 30337919.
- ^ Farrar JD, Smith JD, Murphy TL, Leung S, Stark GR, Murphy KM (July 2000). "Selective loss of type I interferon-induced STAT4 activation caused by a minisatellite insertion in mouse Stat2". Nature Immunology. 1 (1): 65–9. doi:10.1038/76932. PMID 10881177. S2CID 38817062.
- ^ Takaoka A, Mitani Y, Suemori H, Sato M, Yokochi T, Noguchi S, et al. (June 2000). "Cross talk between interferon-gamma and -alpha/beta signaling components in caveolar membrane domains". Science. 288 (5475): 2357–60. Bibcode:2000Sci...288.2357T. doi:10.1126/science.288.5475.2357. PMID 10875919.
- ^ Jewell NA, Cline T, Mertz SE, Smirnov SV, Flaño E, Schindler C, et al. (November 2010). "Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo". Journal of Virology. 84 (21): 11515–22. doi:10.1128/JVI.01703-09. PMC 2953143. PMID 20739515.
- ^ Ashour J, Morrison J, Laurent-Rolle M, Belicha-Villanueva A, Plumlee CR, Bernal-Rubio D, et al. (November 2010). "Mouse STAT2 restricts early dengue virus replication". Cell Host & Microbe. 8 (5): 410–21. doi:10.1016/j.chom.2010.10.007. PMC 3310429. PMID 21075352.
- ^ Tripathi S, Balasubramaniam VR, Brown JA, Mena I, Grant A, Bardina SV, et al. (March 2017). "A novel Zika virus mouse model reveals strain specific differences in virus pathogenesis and host inflammatory immune responses". PLOS Pathogens. 13 (3): e1006258. doi:10.1371/journal.ppat.1006258. PMC 5373643. PMID 28278235.
- ^ Yoshikawa R, Sakabe S, Urata S, Yasuda J (May 2019). "Species-Specific Pathogenicity of Severe Fever with Thrombocytopenia Syndrome Virus Is Determined by Anti-STAT2 Activity of NSs". Journal of Virology. 93 (10). doi:10.1128/JVI.02226-18. PMC 6498056. PMID 30814285.
- ^ Münz C (2014). "Dendritic cells during Epstein Barr virus infection". Frontiers in Microbiology. 5: 308. doi:10.3389/fmicb.2014.00308. PMC 4064564. PMID 24999343.
- ^ Hambleton S, Goodbourn S, Young DF, Dickinson P, Mohamad SM, Valappil M, et al. (February 2013). "STAT2 deficiency and susceptibility to viral illness in humans". Proceedings of the National Academy of Sciences of the United States of America. 110 (8): 3053–8. Bibcode:2013PNAS..110.3053H. doi:10.1073/pnas.1220098110. PMC 3581986. PMID 23391734.
- ^ Gruber C, Martin-Fernandez M, Ailal F, Qiu X, Taft J, Altman J, et al. (May 2020). "Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy". The Journal of Experimental Medicine. 217 (5). doi:10.1084/jem.20192319. PMC 7201920. PMID 32092142.
- ^ Duncan CJ, Thompson BJ, Chen R, Rice GI, Gothe F, Young DF, et al. (December 2019). "Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2". Science Immunology. 4 (42): eaav7501. doi:10.1126/sciimmunol.aav7501. hdl:20.500.11820/3908eba0-5d5c-404d-b79f-08e6bd93b61d. PMC 7115903. PMID 31836668.
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Further reading
[edit]- Cebulla CM, Miller DM, Sedmak DD (2000). "Viral inhibition of interferon signal transduction". Intervirology. 42 (5–6): 325–30. doi:10.1159/000053968. PMID 10702714. S2CID 22135982.
- Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW (February 2002). "Signaling through the JAK/STAT pathway, recent advances and future challenges". Gene. 285 (1–2): 1–24. doi:10.1016/S0378-1119(02)00398-0. PMID 12039028.
- Fu XY, Schindler C, Improta T, Aebersold R, Darnell JE (August 1992). "The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction". Proceedings of the National Academy of Sciences of the United States of America. 89 (16): 7840–3. Bibcode:1992PNAS...89.7840F. doi:10.1073/pnas.89.16.7840. PMC 49807. PMID 1502204.
- Uddin S, Chamdin A, Platanias LC (October 1995). "Interaction of the transcriptional activator Stat-2 with the type I interferon receptor". The Journal of Biological Chemistry. 270 (42): 24627–30. doi:10.1074/jbc.270.42.24627. PMID 7559568.
- Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, Delafontaine P, Bernstein KE (May 1995). "Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor". Nature. 375 (6528): 247–50. Bibcode:1995Natur.375..247M. doi:10.1038/375247a0. PMID 7746328. S2CID 4272223.
- Sugiyama T, Nishio Y, Kishimoto T, Akira S (March 1996). "Identification of alternative splicing form of Stat2". FEBS Letters. 381 (3): 191–4. doi:10.1016/0014-5793(96)00121-4. PMID 8601453. S2CID 12860058.
- Yan H, Krishnan K, Greenlund AC, Gupta S, Lim JT, Schreiber RD, et al. (March 1996). "Phosphorylated interferon-alpha receptor 1 subunit (IFNaR1) acts as a docking site for the latent form of the 113 kDa STAT2 protein". The EMBO Journal. 15 (5): 1064–74. doi:10.1002/j.1460-2075.1996.tb00444.x. PMC 450004. PMID 8605876.
- Gupta S, Yan H, Wong LH, Ralph S, Krolewski J, Schindler C (March 1996). "The SH2 domains of Stat1 and Stat2 mediate multiple interactions in the transduction of IFN-alpha signals". The EMBO Journal. 15 (5): 1075–84. doi:10.1002/j.1460-2075.1996.tb00445.x. PMC 450005. PMID 8605877.
- Li X, Leung S, Qureshi S, Darnell JE, Stark GR (March 1996). "Formation of STAT1-STAT2 heterodimers and their role in the activation of IRF-1 gene transcription by interferon-alpha". The Journal of Biological Chemistry. 271 (10): 5790–4. doi:10.1074/jbc.271.10.5790. PMID 8621447.
- Bhattacharya S, Eckner R, Grossman S, Oldread E, Arany Z, D'Andrea A, Livingston DM (September 1996). "Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha". Nature. 383 (6598): 344–7. Bibcode:1996Natur.383..344B. doi:10.1038/383344a0. PMID 8848048. S2CID 4306588.
- Horvath CM, Stark GR, Kerr IM, Darnell JE (December 1996). "Interactions between STAT and non-STAT proteins in the interferon-stimulated gene factor 3 transcription complex". Molecular and Cellular Biology. 16 (12): 6957–64. doi:10.1128/mcb.16.12.6957. PMC 231699. PMID 8943351.
- Bluyssen HA, Levy DE (February 1997). "Stat2 is a transcriptional activator that requires sequence-specific contacts provided by stat1 and p48 for stable interaction with DNA". The Journal of Biological Chemistry. 272 (7): 4600–5. doi:10.1074/jbc.272.7.4600. PMID 9020188.
- Li X, Leung S, Kerr IM, Stark GR (April 1997). "Functional subdomains of STAT2 required for preassociation with the alpha interferon receptor and for signaling". Molecular and Cellular Biology. 17 (4): 2048–56. doi:10.1128/mcb.17.4.2048. PMC 232052. PMID 9121453.
- Martinez-Moczygemba M, Gutch MJ, French DL, Reich NC (August 1997). "Distinct STAT structure promotes interaction of STAT2 with the p48 subunit of the interferon-alpha-stimulated transcription factor ISGF3". The Journal of Biological Chemistry. 272 (32): 20070–6. doi:10.1074/jbc.272.32.20070. PMID 9242679.
- Mowen K, David M (November 1998). "Role of the STAT1-SH2 domain and STAT2 in the activation and nuclear translocation of STAT1". The Journal of Biological Chemistry. 273 (46): 30073–6. doi:10.1074/jbc.273.46.30073. PMID 9804758.
- Dumler I, Kopmann A, Wagner K, Mayboroda OA, Jerke U, Dietz R, et al. (August 1999). "Urokinase induces activation and formation of Stat4 and Stat1-Stat2 complexes in human vascular smooth muscle cells". The Journal of Biological Chemistry. 274 (34): 24059–65. doi:10.1074/jbc.274.34.24059. PMID 10446176.
- Paulson M, Pisharody S, Pan L, Guadagno S, Mui AL, Levy DE (September 1999). "Stat protein transactivation domains recruit p300/CBP through widely divergent sequences". The Journal of Biological Chemistry. 274 (36): 25343–9. doi:10.1074/jbc.274.36.25343. PMID 10464260.
- Gupta S, Jiang M, Pernis AB (October 1999). "IFN-alpha activates Stat6 and leads to the formation of Stat2:Stat6 complexes in B cells". Journal of Immunology. 163 (7): 3834–41. doi:10.4049/jimmunol.163.7.3834. PMID 10490982. S2CID 255676952.
- Vila-Coro AJ, Rodríguez-Frade JM, Martín De Ana A, Moreno-Ortíz MC, Martínez-A C, Mellado M (October 1999). "The chemokine SDF-1alpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway". FASEB Journal. 13 (13): 1699–710. doi:10.1096/fasebj.13.13.1699. PMID 10506573. S2CID 13251398.
External links
[edit]- STAT2+Transcription+Factor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- FactorBook STAT2
This article incorporates text from the United States National Library of Medicine, which is in the public domain.