STAT2 Is a Pervasive Cytokine Regulator due to Its Inhibition of STAT1 in Multiple Signaling Pathways

PLoS Biology

Volumn 14, Issue 10, 2016, Pages

  Ho, Johnathan ^a   Pelzel, Christin ^a   Begitt, Andreas ^a   Mee, Maureen ^a   Elsheikha, Hany M ^b   Scott, David J ^a,c,d   Vinkemeier, Uwe ^a  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^b UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^c RUTHERFORD APPLETON LABORATORY   (United Kingdom)

^d RUTHERFORD APPLETON LABORATORY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOKINE; DIMER; GAMMA INTERFERON; INTERFERON; INTERLEUKIN 27; INTERLEUKIN 6; KARYOPHERIN ALPHA; MAJOR HISTOCOMPATIBILITY ANTIGEN; STAT1 PROTEIN; STAT2 PROTEIN; STAT3 PROTEIN; DNA; PROTEIN BINDING;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTIGEN EXPRESSION; ARTICLE; CONTROLLED STUDY; DIMERIZATION; DNA BINDING; EFFECTOR CELL; ENZYME ACTIVITY; GENE ACTIVATION; GENE EXPRESSION; GENE REPRESSION; GENE TRANSLOCATION; IMMUNOSENESCENCE; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; NUCLEAR IMPORT; PARASITE IMMUNITY; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN DOMAIN; PROTEIN INTERACTION; PROTEIN PHOSPHORYLATION; SIGNAL TRANSDUCTION; STAT1 GENE; STAT2 GENE; STAT3 GENE; TRANSCRIPTION REGULATION; ANIMAL; ANTAGONISTS AND INHIBITORS; BINDING SITE; CELL NUCLEUS; HUMAN; METABOLISM; PHOSPHORYLATION; PHYSIOLOGY;

ANIMALS; BINDING SITES; CELL NUCLEUS; DIMERIZATION; DNA; GENE EXPRESSION; HUMANS; INTERFERON-GAMMA; PHOSPHORYLATION; PROTEIN BINDING; PROTEIN CONFORMATION; SIGNAL TRANSDUCTION; STAT1 TRANSCRIPTION FACTOR; STAT2 TRANSCRIPTION FACTOR;

EID: 84995595388     PISSN: 15449173     EISSN: 15457885     Source Type: Journal    
DOI: 10.1371/journal.pbio.2000117     Document Type: Article

References (56)

1. O'Shea JJ, Plenge R, JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity2012; 36: 542–50. doi: 10.1016/j.immuni.2012.03.01422520847
2. Stark GR, Darnell JE, Jr.The JAK-STAT pathway at twenty. Immunity2012; 36: 503–14. doi: 10.1016/j.immuni.2012.03.01322520844
3. Levy DE, Darnell JE, JrStats: transcriptional control and biological impact. Nat. Rev. Mol. Cell. Biol. 2002; 3: 651–62. doi: 10.1038/nrm90912209125
4. Vinkemeier U, Moarefi I, Darnell JE, JrKuriyan J, Structure of the amino-terminal protein interaction domain of STAT-4. Science1998; 279: 1048–52. doi: 10.1126/science.279.5353.10489461439
5. Mao X, Ren Z, Parker GN, Sondermann H, Pastorello MA, Wang W, et al. Structural bases of unphosphorylated STAT1 association and receptor binding. Mol. Cell2005; 17: 761–71. doi: 10.1016/j.molcel.2005.02.02115780933
6. Chen X, Vinkemeier U, Zhao Y, Jeruzalmi D, Darnell JE Jr, Kuriyan J, Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell1998; 93: 827–39. doi: 10.1016/s0092-8674(00)81443-99630226
7. Vinkemeier U, Getting the message across, STAT! Design principles of a molecular signaling circuit. J. Cell Biol. 2004; 167: 197–201. doi: 10.1083/jcb.20040716315504906
8. Schroder K, Hertzog PJ, Ravasi T, Hume DA, Interferon-gamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 2004; 75: 163–189. doi: 10.1189/jlb.060325214525967
9. Linossi EM, Nicholson SE, Kinase inhibition, competitive binding and proteasomal degradation: resolving the molecular function of the suppressor of cytokine signaling (SOCS) proteins. Immunol. Rev. 2015; 266: 123–33. doi: 10.1111/imr.1230526085211
10. Delgoffe GM, Murray PJ, Vignali DAA, Interpreting mixed signals; the cell’s cytokine conundrum. Curr. Op. Immunol. 2011; 23: 632–8. doi: 10.1016/j.coi.2011.07.01321852079
11. Ehret GB, Reichenbach P, Schindler U, Horvath CM, Fritz S, Nabholz M, et al. DNA binding specificity of different STAT proteins. Comparison of in vitro specificity with natural target sites. J. Biol. Chem. 2001; 276: 6675–88. doi: 10.1074/jbc.M00174820011053426
12. Hirahara K, Onodera A, Villarino AV, Bonelli M, Sciumè G, Laurence A, et al. Asymmetric action of STAT transcription factors drives transcriptional outputs and cytokine specificity. Immunity2015; 42: 877–89. doi: 10.1016/j.immuni.2015.04.01425992861
13. Steen HC, Gamero AM, The role of signal transducer and activator of transcription-2 in the interferon response. J. Interferon Cytokine Res. 2012; 32: 103–10. doi: 10.1089/jir.2011.009922280068
14. Park C, Li S, Cha E, Schindler C, Immune response in Stat2 knockout mice. Immunity2000; 13: 795–804. doi: 10.1016/s1074-7613(00)00077-711163195
15. Hambleton S, Goodbourne S, Young DF, Dickinson P, Mohamad SM, Valippil M, et al. STAT2 deficiency and susceptibility to viral illness in humans. Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 3053–8. doi: 10.1073/pnas.122009811023391734
16. Karaghiosoff M, Steinborn R, Kovarik P, Kriegshäuser G, Baccarini M, Donabauer B, et al. Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock. Nat. Immunol. 2003; 4: 471–7. doi: 10.1038/ni91012679810
17. Alazawi W, Heath H, Waters JA, Woodfin A, O’Brien AJ, Scarzello AJ, et al. Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis. Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 8656–61. doi: 10.1073/pnas.122165211023653476
18. Banninger G, Reich NC, STAT2 nuclear trafficking. J. Biol. Chem. 2004; 279: 39199–206. doi: 10.1074/jbc.M40081520015175343
19. Frahm T, Hauser H, Köster M, IFN-type-I-mediated signaling is regulated by modulation of STAT2 nuclear export. J. Cell Sci. 2006; 119: 1092–1104. doi: 10.1242/jcs.0282216507591
20. Meissner T, Krause E, Vinkemeier U, Ratjadone and leptomycin B block CRM1-dependent nuclear export by identical mechanisms. FEBS Lett. 2004, 576: 27–30. doi: 10.1016/j.febslet.2004.08.05615474004
21. Begitt A, Droescher M, Meyer T, Schmid CD, Maker M, Antunes F, et al. STAT1-cooperative DNA binding distinguishes type 1 from type 2 interferon signaling. Nat. Immunol. 2014; 15: 168–76. doi: 10.1038/ni.279424413774
22. Wenta N, Strauss H, Meyer S, Vinkemeier U, Tyrosine phosphorylation regulates the partitioning of STAT1 between different dimer conformations. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 9238–43. doi: 10.1073/pnas.080213010518591661
23. Melén K, Kinnunen L, Julkunen I, Arginine/lysine-rich structural element is involved in interferon-induced nuclear import of STATs. J. Biol. Chem. 2001; 276: 16447–55. doi: 10.1074/jbc.M00882120011150296
24. Hu X, Herrero C, Li WP, Antoniv TT, Falck-Pedersen E, Koch AE, et al. Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation. Nat. Immunol. 2002; 3: 859–66. doi: 10.1038/ni82812172544
25. Fagerlund R, Melén K, Kinnunen L, Julkunen I, Arginine/lysine-rich nuclear localisation signals mediate interactions between dimeric STATs and importin alpha 5. J. Biol. Chem. 2002; 277: 30072–8. doi: 10.1074/jbc.M20294320012048190
26. Nardozzi J, Wenta N, Yasuhara N, Vinkemeier U, Cingolani G, Molecular basis for the recognition of phosphorylated STAT1 by importin alpha5. J. Mol. Biol. 2010; 402: 83–100. doi: 10.1016/j.jmb.2010.07.01320643137
27. Majoros A, Platanitis E, Szappanos D, Cheon H, Vogl C, Shukla P, et al. Response to interferons and antibacterial innate immunity in the absence of tyrosine‐phosphorylated STAT1. EMBO Rep. 2016; 17: 367–82. doi: 10.15252/embr.20154072626882544
28. Heim MH, Kerr IM, Stark GR, Darnell JE, JrContribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway. Science1995; 267: 1347–9. doi: 10.1126/science.78714327871432
29. Shuai K, Ziemiecki A, Wilks AF, Harpur AG, Sadowski HB, Gilman MZ, et al. Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and STAT proteins. Nature1993; 366: 580–3. doi: 10.1038/366580a07504784
30. Morrow AN, Schmeisser H, Tsuno T, Zoon KC, A novel role for IFN-stimulated gene factor 3II in IFN-γ signaling and induction of antiviral activity in human cells. J. Immunol. 2011; 186: 1685–93. doi: 10.4049/jimmunol.100135921178011
31. Braumüller H, Wieder T, Brenner E, Aßmann S, Hahn M, Alkhaled M, et al. T-helper-1-cell cytokines drive cancer into senescence. Nature2013; 494: 361–65. doi: 10.1038/nature1182423376950
32. Pifer R, Yarovinsky F, Innate responses to Toxoplasma gondii in mice and humans. Trends Parasitol. 2011; 27: 388–93. doi: 10.1016/j.pt.2011.03.00921550851
33. Melo MB, Nguyen QP, Cordeiro C, Hassan MA, Yang N, McKell R, et al. Transcriptional analysis of murine macrophages infected with different Toxoplasma strains identifies novel regulation of host signaling pathways. PLoS Pathog. 2013; 9: e1003779. doi: doi: 10.1371/journal.ppat.100377924367253
34. Davidson S, Maini MK, Wack A, Disease-promoting effects of type I interferons in viral, bacterial, and coinfections. J. Interferon Cytokine Res. 2015; 35: 252–64. doi: 10.1089/jir.2014.022725714109
35. Lorsbach RB, Murphy WJ, Lowenstein CJ, Snyder SH, Russell SW, Expression of the nitric oxide synthase gene in mouse macrophages activated for tumour killing. Molecular basis for the synergy between interferon-gamma and lipopolysaccharide. J. Biol. Chem. 1993; 268: 1908–13. 7678412
36. Brocke-Heidrich K, Kretzschmar AK, Pfeifer G, Hanze C, Löffler D, Koczan D, et al. Interleukin-6–dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family–independent survival pathway closely associated with Stat3 activation. Blood2004; 103: 242–51. 12969979
37. Fu XY, Schindler C, Improta T, Aebersold R, Darnell JE, JrThe proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction. Proc. Natl. Acad. Sci. U.S.A. 1992; 89: 7840–3. doi: 10.1073/pnas.89.16.78401502204
38. Wan CK, Andraski AB, Spolski R, Li P, Karzemian M, Oh J, et al. Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells. Proc. Natl. Acad. Sci. U.S.A. 2015; 112: 9394–9. doi: 10.1073/pnas.151171111226170288
39. Dupuis S, Döffinger R, Picard C, Fieschi C, Altare F, Jouanguy E, et al. Human interferon-gamma-mediated immunity is a genetically controlled continuous trait that determines the outcome of mycobacterial invasion. Immunol. Rev. 2000; 178: 129–37. doi: 10.1034/j.1600-065x.2000.17810.x11213797
40. Widschwendter A, Tonko-Geymayer S, Welte T, Daxenbichler G, Marth C, Doppler W, Prognostic significance of signal transducer and activator of transcription 1 activation in breast cancer. Clin. Cancer Res. 2002; 8: 3065–74. 12374673
41. Cheon H, Holvey-Bates EG, Schoggins JW, Forster S, Hertzog P, Imanaka N, et al. IFNbeta-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. EMBO J. 2013; 32: 2751–63. doi: 10.1038/emboj.2013.20324065129
42. Hirata O, Okada S, Tsumura M, Kagawa R, Miki M, Kawaguchi H, et al. Heterozygosity for the Y701C STAT1 mutation in a multiplex kindred with multifocal osteomyelitis. Haematologica2013; 98: 1641–9. doi: 10.3324/haematol.2013.08374123585529
43. He J, Shi J, Xu X, Zhang W, Wang Y, Chen X, et al. STAT3 mutations correlated with hyper-IgE syndrome lead to blockage of IL-6/STAT3 signalling pathway. J. Biosci. 2012; 37: 243–57. doi: 10.1007/s12038-012-9202-x22581330
44. Mohr A, Fahrenkamp D, Rinis N, Müller-Newen G, Dominant-negative activity of the STAT3-Y705F mutant depends on the N-terminal domain. Cell Commun. Signal. 2013; 11: 83. doi:doi: 10.1186/1478-811X-11-8324192293
45. Gough DJ, Messina NL, Hii L, Gould JA, Sabapathy K, Robertson AP, et al. Functional crosstalk between type I and II interferon through the regulated expression of STAT1. PLoS Biol. 2011; 8(4): e1000361. doi:doi: 10.1371/journal.pbio.1000361
46. Duncan CJ, Mohamad SM, Young DF, Skelton AJ, Leahy TR, Munday DC, et al. Human IFNAR2 deficiency: Lessons for antiviral immunity. Sci. Transl. Med. 2015; 7: 307ra154. doi: doi: 10.1126/scitranslmed.aac422726424569
47. Begitt A, Droescher M, Knobeloch KP, Vinkemeier U, SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ. Blood2011; 118: 1002–7. doi: 10.1182/blood-2011-04-34793021636857
48. Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp. Med. 2011; 208: 1635–48. doi: 10.1084/jem.2011095821727188
49. Van der Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LA, Gilissen C, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N. Engl. J. Med. 2011; 365: 54–61. doi: 10.1056/NEJMoa110010221714643
50. Xu W, Edwards MR, Borek DM, Feagins AR, Mittal A, Alinger JB, et al. Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. Cell Host Microbe2014; 16: 187–200. doi: 10.1016/j.chom.2014.07.00825121748
51. Semper C, Leitner NR, Lassnig C, Parrini M, Mahlakõiv T, Rammerstorfer M, et al. STAT1β is not dominant negative and is capable of contributing to gamma interferon-dependent innate immunity. Mol. Cell. Biol. 2014; 34: 2235–48. doi: 10.1128/MCB.00295-1424710278
52. Ray A, Dittel BN, Isolation of mouse peritoneal cavity cells. J. Vis. Exp. 2010; 35: e1488. doi:doi: 10.3791/148820110936
53. Pellegrini S, John J, Shearer M, Kerr IM, Stark GR, Use of a selectable marker regulated by alpha interferon to obtain mutations in the signaling pathway. Mol. Cell. Biol. 1989; 9: 4605–12. doi: 10.1128/mcb.9.11.46052513475
54. Elsheikha HM, Rosenthal BM, Murphy AJ, Dunams DB, Neelis DA, Mansfield LS, Generally applicable methods to purify intracellular coccidian from cell cultures and to quantify purification efficacy using quantitative PCR. Vet. Parasitol. 2006; 135: 223–34. doi: 10.1016/j.vetpar.2005.09.01416280197
55. Mcleod R, Remington JS, Studies on the specificity of killing of intracellular pathogens by macrophages. Cell. Immunol. 1977; 1: 156–74. doi: 10.1016/0008-8749(77)90238-671951
56. Pelzel C, Begitt A, Wenta N, Vinkemeier U, Evidence against a role for β-arrestin 1 in STAT1 dephosphorylation and the inhibition of interferon-γ signaling. Mol. Cell2013; 50: 149–156. doi: 10.1016/j.molcel.2013.02.02423582260