Canonical and non-canonical aspects of JAK-STAT signaling: Lessons from interferons for cytokine responses

Frontiers in Immunology

Volumn 8, Issue JAN, 2017, Pages

  Majoros, Andrea ^a   Platanitis, Ekaterini ^a   Kernbauer Hölzl, Elisabeth ^a   Rosebrock, Felix ^a   Müller, Mathias ^b   Decker, Thomas ^a  

^a UNIVERSITY OF VIENNA   (Austria)

^b UNIVERSITY OF VETERINARY MEDICINE   (Austria)

Author keywords

Innate immunity; Interferon; JAK STAT; Non canonical; Signal transduction

Indexed keywords

GAMMA INTERFERON; INTERFERON REGULATORY FACTOR 9; INTERLEUKIN 10; JANUS KINASE; PROTEIN KINASE TYK2; STAT PROTEIN; STAT2 PROTEIN;

CANONICAL ANALYSIS; CHLAMYDIA PNEUMONIAE; CYTOKINE RESPONSE; FRANCISELLA TULARENSIS; GENE ACTIVATION; GENE EXPRESSION REGULATION; GENE MUTATION; IMMUNOSTIMULATION; INNATE IMMUNITY; LEGIONELLA PNEUMOPHILA; LISTERIA MONOCYTOGENES; MICROBIAL IMMUNITY; MYCOBACTERIUM TUBERCULOSIS; NATURAL KILLER CELL; NONHUMAN; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REVIEW; SALMONELLA ENTERICA SEROVAR TYPHIMURIUM; SIGNAL TRANSDUCTION; STREPTOCOCCUS INFECTION; TRANSCRIPTION INITIATION; TRANSCRIPTION REGULATION;

EID: 85012168846     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2017.00029     Document Type: Review

References (161)

1. Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci (1957) 147:258-67. doi:10.1098/rspb.1957.0048
2. Levy DE, Darnell JE Jr. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol (2002) 3:651-62. doi:10.1038/nrm909
3. Borden EC, Sen GC, Uze G, Silverman RH, Ransohoff RM, Foster GR, et al. Interferons at age 50: past, current and future impact on biomedicine. Nat Rev Drug Discov (2007) 6:975-90. doi:10.1038/nrd2422
4. Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol (2014) 32:513-45. doi:10.1146/annurev-immunol-032713-120231
5. Pestka S, Krause CD, Walter MR. Interferons, interferon-like cytokines, and their receptors. Immunol Rev (2004) 202:8-32. doi:10.1111/j.0105-2896.2004.00204.x
6. Tough DF, Zhang X, Sprent J. An IFN-gamma-dependent pathway controls stimulation of memory phenotype CD8+ T cell turnover in vivo by IL-12, IL-18, and IFN-gamma. J Immunol (2001) 166:6007-11. doi:10.4049/jimmunol.166.10.6007
7. Brinkmann V, Geiger T, Alkan S, Heusser CH. Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells. J Exp Med (1993) 178:1655-63. doi:10.1084/jem.178.5.1655
8. Biron CA. Interferons a and β as immune regulators - a new look. Immunity (2001) 14:661-4. doi:10.1016/S1074-7613(01)00154-6
9. Rauch I, Müller M, Decker T. The regulation of inflammation by interferons and their STATs. JAKSTAT (2013) 2:e23820. doi:10.4161/jkst.23820
10. Coccia EM, Battistini A. Early IFN type I response: learning from microbial evasion strategies. Semin Immunol (2015) 27:85-101. doi:10.1016/j.smim.2015.03.005
11. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol (2006) 6:836-48. doi:10.1038/nri1961
12. Crow YJ, Manel N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat Rev Immunol (2015) 15:429-40. doi:10.1038/nri3850
13. Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation: the type I interferonopathies, a conceptual overview. J Exp Med (2016) 213:2527-38. doi:10.1084/jem.20161596
14. Decker T, Muller M, Stockinger S. The yin and yang of type I interferon activity in bacterial infection. Nat Rev Immunol (2005) 5:675-87. doi:10.1038/nri1684
15. Trinchieri G. Type I interferon: friend or foe? J Exp Med (2010) 207:2053-63. doi:10.1084/jem.20101664
16. Buß C, Opitz B, Hocke AC, Lippmann J, van Laak V, Hippenstiel S, et al. Essential role of mitochondrial antiviral signaling, IFN regulatory factor (IRF)3, and IRF7 in Chlamydophila pneumoniae-mediated IFN-β response and control of bacterial replication in human endothelial cells. J Immunol (2010) 184:3072-8. doi:10.4049/jimmunol.0902947
17. Plumlee CR, Lee C, Beg AA, Decker T, Shuman HA, Schindler C. Interferons direct an effective innate response to Legionella pneumophila infection. J Biol Chem (2009) 284:30058-66. doi:10.1074/jbc.M109.018283
18. Freudenberg MA, Merlin T, Kalis C, Chvatchko Y, Stubig H, Galanos C. Cutting edge: a murine, IL-12-independent pathway of IFN-gamma induction by gram-negative bacteria based on STAT4 activation by Type I IFN and IL-18 signaling. J Immunol (2002) 169:1665-8. doi:10.4049/jimmunol.169.4.1665
19. Mancuso G, Midiri A, Biondo C, Beninati C, Zummo S, Galbo R, et al. Type I IFN signaling is crucial for host resistance against different species of pathogenic bacteria. J Immunol (2007) 178:3126-33. doi:10.4049/jimmunol.178.5.3126
20. Mancuso G, Gambuzza M, Midiri A, Biondo C, Papasergi S, Akira S, et al. Bacterial recognition by TLR7 in the lysosomes of conventional dendritic cells. Nat Immunol (2009) 10:587-94. doi:10.1038/ni.1733
21. Castiglia V, Piersigilli A, Ebner F, Janos M, Goldmann O, Damböck U, et al. Type I Interferon signaling prevents IL-1β-driven lethal systemic hyperinflammation during invasive bacterial infection of soft tissue. Cell Host Microbe (2016) 19:375-87. doi:10.1016/j.chom.2016.02.003
22. Couturier N, Bucciarelli F, Nurtdinov RN, Debouverie M, Lebrun-Frenay C, Defer G, et al. Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility. Brain (2011) 134:693-703. doi:10.1093/brain/awr010
23. Dyment DA, Cader MZ, Chao MJ, Lincoln MR, Morrison KM, Disanto G, et al. Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene. Neurology (2012) 79:406-11. doi:10.1212/WNL.0b013e3182616fc4
24. Liu JZ, Almarri MA, Gaffney DJ, Mells GF, Jostins L, Cordell HJ, et al. Dense fine-mapping study identifies new susceptibility loci for primary biliary cirrhosis. Nat Genet (2012) 44:1137-41. doi:10.1038/ng.2395
25. Peluso C, Christofolini DM, Goldman CS, Mafra FA, Cavalcanti V, Barbosa CP, et al. TYK2 rs34536443 polymorphism is associated with a decreased susceptibility to endometriosis-related infertility. Hum Immunol (2013) 74:93-7. doi:10.1016/j.humimm.2012.09.007
26. Minegishi Y, Saito M, Morio T, Watanabe K, Agematsu K, Tsuchiya S, et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity (2006) 25:745-55. doi:10.1016/j.immuni.2006.09.009
27. Kreins AY, Ciancanelli MJ, Okada S, Kong X-F, Ramírez-Alejo N, Kilic SS, et al. Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome. J Exp Med (2015) 212:1641-62. doi:10.1084/jem.20140280
28. Bach EA, Aguet M, Schreiber RD. The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol (1997) 15:563-91. doi:10.1146/annurev.immunol.15.1.563
29. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol (2004) 75:163-89. doi:10.1189/jlb.0603252
30. Lazarevic V, Glimcher LH, Lord GM. T-bet: a bridge between innate and adaptive immunity. Nat Rev Immunol (2013) 13:777-89. doi:10.1038/nri3536
31. MacMicking JD. Interferon-inducible effector mechanisms in cell-autonomous immunity. Nat Rev Immunol (2012) 12:367-82. doi:10.1038/nri3210
32. Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-gamma. Annu Rev Immunol (1997) 15:749-95. doi:10.1146/annurev.immunol.15.1.749
33. Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R, et al. Immune response in mice that lack the interferon-gamma receptor. Science (1993) 259:1742-5. doi:10.1126/science.8456301
34. Dalton DK, Pitts Meek S, Keshav S, Figari IS, Bradley A, Stewart TA. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science (1993) 259:1739-42. doi:10.1126/science.8456300
35. Casanova J-L, Abel L. The human model: a genetic dissection of immunity to infection in natural conditions. Nat Rev Immunol (2004) 4:55-66. doi:10.1038/nri1264
36. Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol (2003) 4:69-77. doi:10.1038/ni875
37. Donnelly RP, Kotenko SV. Interferon-lambda: a new addition to an old family. J Interferon Cytokine Res (2010) 30:555-64. doi:10.1089/jir.2010.0078
38. Uzé G, Monneron D. IL-28 and IL-29: newcomers to the interferon family. Biochimie (2007) 89:729-34. doi:10.1016/j.biochi.2007.01.008
39. Crotta S, Davidson S, Mahlakoiv T, Desmet CJ, Buckwalter MR, Albert ML, et al. Type I and type III interferons drive redundant amplification loops to induce a transcriptional signature in influenza-infected airway epithelia. PLoS Pathog (2013) 9:e1003773. doi:10.1371/journal.ppat.1003773
40. Ghoreschi K, Laurence A, O'Shea JJ. Janus kinases in immune cell signaling. Immunol Rev (2009) 228:273-87. doi:10.1111/j.1600-065X.2008.00754.x
41. O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med (2015) 66:311-28. doi:10.1146/annurev-med-051113-024537
42. Strobl B, Stoiber D, Sexl V, Mueller M. Tyrosine kinase 2 (TYK2) in cytokine signalling and host immunity. Front Biosci (Landmark Ed) (2011) 16:3224. doi:10.2741/3908
43. Velazquez L, Fellous M, Stark GR, Pellegrini S. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell (1992) 70:313-22. doi:10.1016/0092-8674(92)90105-L
44. Gauzzi MC, Velazquez L, McKendry R, Mogensen KE, Fellous M, Pellegrini S. Interferon-alpha-dependent activation of Tyk2 requires phosphorylation of positive regulatory tyrosines by another kinase. J Biol Chem (1996) 271:20494-500. doi:10.1074/jbc.271.34.20494
45. Rani MR, Leaman DW, Han Y, Leung S, Croze E, Fish EN, et al. Catalytically active TYK2 is essential for interferon-beta-mediated phosphorylation of STAT3 and interferon-alpha receptor-1 (IFNAR-1) but not for activation of phosphoinositol 3-kinase. J Biol Chem (1999) 274:32507-11. doi:10.1074/jbc.274.45.32507
46. Rani MR, Gauzzi C, Pellegrini S, Fish EN, Wei T, Ransohoff RM. Induction of beta-R1/I-TAC by interferon-beta requires catalytically active TYK2. J Biol Chem (1999) 274:1891-7. doi:10.1074/jbc.274.4.1891
47. Ragimbeau J, Dondi E, Alcover A, Eid P, Uzé G, Pellegrini S. The tyrosine kinase Tyk2 controls IFNAR1 cell surface expression. EMBO J (2003) 22:537-47. doi:10.1093/emboj/cdg038
48. Kumar KGS, Varghese B, Banerjee A, Baker DP, Constantinescu SN, Pellegrini S, et al. Basal ubiquitin-independent internalization of interferon alpha receptor is prevented by Tyk2-mediated masking of a linear endocytic motif. J Biol Chem (2008) 283:18566-72. doi:10.1074/jbc.M800991200
49. Karaghiosoff M, Neubauer H, Lassnig C, Kovarik P, Schindler H, Pircher H, et al. Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity (2000) 13:549-60. doi:10.1016/S1074-7613(00)00054-6
50. Shimoda K, Kato K, Aoki K, Matsuda T, Miyamoto A, Shibamori M, et al. Tyk2 plays a restricted role in IFNa signaling, although it is required for IL-12-mediated T cell function. Immunity (2000) 13:561-71. doi:10.1016/S1074-7613(00)00055-8
51. Prchal-Murphy M, Semper C, Lassnig C, Wallner B, Gausterer C, Teppner-Klymiuk I, et al. TYK2 kinase activity is required for functional type I interferon responses in vivo. PLoS One (2012) 7:e39141. doi:10.1371/journal.pone.0039141
52. Prchal-Murphy M, Witalisz-Siepracka A, Bednarik KT, Putz EM, Gotthardt D, Meissl K, et al. In vivo tumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity. Oncoimmunology (2015) 4:e1047579. doi:10.1080/2162402X.2015.1047579
53. Potla R, Koeck T, Wegrzyn J, Cherukuri S, Shimoda K, Baker DP, et al. Tyk2 tyrosine kinase expression is required for the maintenance of mitochondrial respiration in primary Pro-B lymphocytes. Mol Cell Biol (2006) 26:8562-71. doi:10.1128/MCB.00497-06
54. Vogl C, Flatt T, Fuhrmann B, Hofmann E, Wallner B, Stiefvater R, et al. Transcriptome analysis reveals a major impact of JAK protein tyrosine kinase 2 (Tyk2) on the expression of interferon-responsive and metabolic genes. BMC Genomics (2010) 11:199. doi:10.1186/1471-2164-11-199
55. Derecka M, Gornicka A, Koralov SB, Szczepanek K, Morgan M, Raje V, et al. Tyk2 and Stat3 regulate brown adipose tissue differentiation and obesity. Cell Metab (2012) 16:814-24. doi:10.1016/j.cmet.2012.11.005
56. Mostafavi S, Yoshida H, Moodley D, LeBoité H, Rothamel K, Raj T, et al. Parsing the interferon transcriptional network and its disease associations. Cell (2016) 164:564-78. doi:10.1016/j.cell.2015.12.032
57. Sigurdsson S, Nordmark G, Göring HH, Lindroos K, Wiman AC, Sturfelt G, et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet (2005) 76:528-37. doi:10.1086/428480
58. Graham DSC, Akil M, Vyse TJ. Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families. Rheumatology (2007) 46:927-30. doi:10.1093/rheumatology/kel449
59. Ban M, Goris A, Lorentzen AR, Baker A, Mihalova T, Ingram G, et al. Replication analysis identifies TYK2 as a multiple sclerosis susceptibility factor. Eur J Hum Genet (2009) 17:1309-13. doi:10.1038/ejhg.2009.41
60. Hellquist A, Järvinen TM, Koskenmies S, Zucchelli M, Orsmark-Pietras C, Berglind L, et al. Evidence for genetic association and interaction between the TYK2 and IRF5 genes in systemic lupus erythematosus. J Rheumatol (2009) 36:1631-8. doi:10.3899/jrheum.081160
61. Sato K, Shiota M, Fukuda S, Iwamoto E, Machida H, Inamine T, et al. Strong evidence of a combination polymorphism of the tyrosine kinase 2 gene and the signal transducer and activator of transcription 3 gene as a DNA-based biomarker for susceptibility to Crohn's disease in the Japanese population. J Clin Immunol (2009) 29:815-25. doi:10.1007/s10875-009-9320-x
62. Suarez-Gestal M, Calaza M, Gonzalez A. Lack of interaction between systemic lupus erythematosus-associated polymorphisms in TYK2 and IRF5. J Rheumatol (2010) 37:676-7. doi:10.1186/ar2990
63. Wang K, Zhang H, Kugathasan S, Annese V, Bradfield JP, Russell RK, et al. Diverse genome-wide association studies associate the IL12/IL23 pathway with Crohn disease. Am J Hum Genet (2009) 84:399-405. doi:10.1016/j.ajhg.2009.01.026
64. Franke A, McGovern DPB, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet (2010) 42:1118-25. doi:10.1038/ng.717
65. Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet (2012) 44:1341-8. doi:10.1038/ng.2467
66. Johnson BA, Wang J, Taylor EM, Caillier SJ, Herbert J, Khan OA, et al. Multiple sclerosis susceptibility alleles in African Americans. Genes Immun (2010) 11:343-50. doi:10.1038/gene.2009.81
67. Mero I-L, Lorentzen AR, Ban M, Smestad C, Celius EG, Aarseth JH, et al. A rare variant of the TYK2 gene is confirmed to be associated with multiple sclerosis. Eur J Hum Genet (2010) 18:502-4. doi:10.1038/ejhg.2009.195
68. Wallace C, Smyth DJ, Maisuria-Armer M, Walker NM, Todd JA, Clayton DG. The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes. Nat Genet (2010) 42:68-71. doi:10.1038/ng.493
69. Li Z, Gakovic M, Ragimbeau J, Eloranta M-L, Rönnblom L, Michel F, et al. Two rare disease-associated Tyk2 variants are catalytically impaired but signaling competent. J Immunol (2013) 190:2335-44. doi:10.4049/jimmunol.1203118
70. Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell (1998) 93:385-95. doi:10.1016/S0092-8674(00)81167-8
71. Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell (1998) 93:397-409. doi:10.1016/S0092-8674(00)81168-X
72. Lacronique V, Boureux A, Valle VD, Poirel H, Quang CT, Mauchauffé M, et al. A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. Science (1997) 278:1309-12. doi:10.1126/science.278.5341.1309
73. Lacronique V, Boureux A, Monni R, Dumon S, Mauchauffé M, Mayeux P, et al. Transforming properties of chimeric TEL-JAK proteins in Ba/F3 cells. Blood (2000) 95:2076-83.
74. Carron C, Cormier F, Janin A, Lacronique V, Giovannini M, Daniel MT, et al. TEL-JAK2 transgenic mice develop T-cell leukemia. Blood (2000) 95:3891-9.
75. Huang LJ, Constantinescu SN, Lodish HF. The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Mol Cell (2001) 8:1327-38. doi:10.1016/S1097-2765(01)00401-4
76. Frenzel K, Wallace TA, McDoom I, Xiao HD, Capecchi MR, Bernstein KE, et al. A functional Jak2 tyrosine kinase domain is essential for mouse development. Exp Cell Res (2006) 312:2735-44. doi:10.1016/j.yexcr.2006.05.004
77. Keil E, Finkenstädt D, Wufka C, Trilling M, Liebfried P, Strobl B, et al. Important scaffold function of the Janus kinase 2 uncovered by a novel mouse model harboring a Jak2 activation loop mutation. Blood (2013) 123:520-9. doi:10.1182/blood-2013-03-492157
78. Boisson-Dupuis S, Kong X-F, Okada S, Cypowyj S, Puel A, Abel L, et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol (2012) 24:1-15. doi:10.1016/j.coi.2012.04.011
79. Casanova J-L, Holland SM, Notarangelo LD. Inborn errors of human JAKs and STATs. Immunity (2012) 36:515-28. doi:10.1016/j.immuni.2012.03.016
80. Boisson B, Quartier P, Casanova J-L. Immunological loss-of-function due to genetic gain-of-function in humans: autosomal dominance of the third kind. Curr Opin Immunol (2015) 32:90-105. doi:10.1016/j.coi.2015.01.005
81. Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood (2016) 127:3154-64. doi:10.1182/blood-2015-11-679902
82. Sharfe N, Nahum A, Newell A, Dadi H, Ngan B, Pereira SL, et al. Fatal combined immunodeficiency associated with heterozygous mutation in STAT1. J Allergy Clin Immunol (2014) 133:807-17. doi:10.1016/j.jaci.2013.09.032
83. Gil MP, Bohn E, O'Guin AK, Ramana CV, Levine B, Stark GR, et al. Biologic consequences of Stat1-independent IFN signaling. Proc Natl Acad Sci U S A (2001) 98:6680-5. doi:10.1073/pnas.111163898
84. Shresta S, Sharar KL, Prigozhin DM, Snider HM, Beatty PR, Harris E. Critical roles for both STAT1-dependent and STAT1-independent pathways in the control of primary dengue virus infection in mice. J Immunol (2005) 175:3946-54. doi:10.4049/jimmunol.175.6.3946
85. George CX, Das S, Samuel CE. Organization of the mouse RNA-specific adenosine deaminase Adar1 gene 5'-region and demonstration of STAT1-independent, STAT2-dependent transcriptional activation by interferon. Virology (2008) 380:338-43. doi:10.1016/j.virol.2008.07.029
86. Johnson AJ, Roehrig JT. New mouse model for dengue virus vaccine testing. J Virol (1999) 73:783-6.
87. Perry ST, Buck MD, Lada SM, Schindler C, Shresta S. STAT2 mediates innate immunity to Dengue virus in the absence of STAT1 via the type I interferon receptor. PLoS Pathog (2011) 7:e1001297. doi:10.1371/journal.ppat.1001297
88. Hahm B, Trifilo MJ, Zuniga EI, Oldstone MB. Viruses evade the immune system through type I interferon-mediated STAT2-dependent, but STAT1-independent, signaling. Immunity (2005) 22:247-57. doi:10.1016/j.immuni.2005.01.005
89. Sarkis PTN, Ying S, Xu R, Yu X-F. STAT1-independent cell type-specific regulation of antiviral APOBEC3G by IFN-alpha. J Immunol (2006) 177:4530-40. doi:10.4049/jimmunol.177.7.4530
90. Lou Y-J, Pan X-R, Jia P-M, Li D, Xiao S, Zhang Z-L, et al. IRF-9/STAT2 [corrected] functional interaction drives retinoic acid-induced gene G expression independently of STAT1. Cancer Res (2009) 69:3673-80. doi:10.1158/0008-5472.CAN-08-4922
91. Bluyssen HAR, Levy DE. Stat2 is a transcriptional activator that requires sequence specific contacts provided by stat1 and p48 for stable interaction with DNA. J Biol Chem (1997) 272:4600-5. doi:10.1074/jbc.272.7.4600
92. Fink K, Martin L, Mukawera E, Chartier S, De Deken X, Brochiero E, et al. IFNβ/TNFα synergism induces a non-canonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH oxidase-mediated airway antiviral response. Cell Res (2013) 23:673-90. doi:10.1038/cr.2013.47
93. Fink K, Grandvaux N. STAT2 and IRF9: beyond ISGF3. JAKSTAT (2013) 2:e27521. doi:10.4161/jkst.27521
94. Blaszczyk K, Nowicka H, Kostyrko K, Antonczyk A, Wesoly J, Bluyssen HAR. The unique role of STAT2 in constitutive and IFN-induced transcription and antiviral responses. Cytokine Growth Factor Rev (2016) 29:71-81. doi:10.1016/j.cytogfr.2016.02.010
95. Stockinger S, Materna T, Stoiber D, Bayr L, Steinborn R, Kolbe T, et al. Production of type I IFN sensitizes macrophages to cell death induced by Listeria monocytogenes. J Immunol (2002) 169:6522-9. doi:10.4049/jimmunol.169.11.6522
96. Henry T, Brotcke A, Weiss DS, Thompson LJ, Monack DM. Type I interferon signaling is required for activation of the inflammasome during Francisella infection. J Exp Med (2007) 204:987-94. doi:10.1084/jem.20062665
97. Tam MA, Rydström A, Sundquist M, Wick MJ. Early cellular responses to Salmonella infection: dendritic cells, monocytes, and more. Immunol Rev (2008) 225:140-62. doi:10.1111/j.1600-065X.2008.00679.x
98. Abdul-Sater AA, Majoros A, Plumlee CR, Perry S, Gu A-D, Lee C, et al. Different STAT transcription complexes drive early and delayed responses to type I IFNs. J Immunol (2015) 195:210-6. doi:10.4049/jimmunol.1401139
99. 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:e201540726. doi:10.15252/embr.201540726
100. Martinez-Moczygemba M, Gutch MJ, French DL, Reich NC. Distinct STAT structure promotes interaction of STAT2 with the p48 subunit of the interferon-alpha-stimulated transcription factor ISGF3. J Biol Chem (1997) 272:20070-6. doi:10.1074/jbc.272.32.20070
101. Kraus TA, Lau JF, Parisien J-P, Horvath CM. A hybrid IRF9-STAT2 protein recapitulates interferon-stimulated gene expression and antiviral response. J Biol Chem (2003) 278:13033-8. doi:10.1074/jbc.M212972200
102. Decker T, Lew DJ, Mirkovitch J, Darnell JEJ. Cytoplasmic activation of GAF, an IFN-gamma-regulated DNA-binding factor. EMBO J (1991) 10:927-32.
103. Varinou L, Ramsauer K, Karaghiosoff M, Kolbe T, Pfeffer K, Muller M, et al. Phosphorylation of the Stat1 transactivation domain is required for full-fledged IFN-gamma-dependent innate immunity. Immunity (2003) 19:793-802. doi:10.1016/S1074-7613(03)00322-4
104. Ramsauer K, Farlik M, Zupkovitz G, Seiser C, Kroger A, Hauser H, et al. Distinct modes of action applied by transcription factors STAT1 and IRF1 to initiate transcription of the IFN-gamma-inducible gbp2 gene. Proc Natl Acad Sci U S A (2007) 104:2849-54. doi:10.1073/pnas.0610944104
105. Rogers RS, Horvath CM, Matunis MJ. SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation. J Biol Chem (2003) 278:30091-7. doi:10.1074/jbc.M301344200
106. Song L, Bhattacharya S, Yunus AA, Lima CD, Schindler C. Stat1 and SUMO modification. Blood (2006) 108:3237-44. doi:10.1182/blood-2006-04-020271
107. Ungureanu D, Vanhatupa S, Kotaja N, Yang J, Aittomaki S, Jänne OA, et al. PIAS proteins promote SUMO-1 conjugation to STAT1. Blood (2003) 102:3311-3. doi:10.1182/blood-2002-12-3816
108. Begitt A, Droescher M, Knobeloch K-P, Vinkemeier U. SUMO conjugation of STAT1 protects cells from hyperresponsiveness to IFNγ. Blood (2011) 118:1002-7. doi:10.1182/blood-2011-04-347930
109. Droescher M, Begitt A, Marg A, Zacharias M, Vinkemeier U. Cytokine-induced paracrystals prolong the activity of signal transducers and activators of transcription (STAT) and provide a model for the regulation of protein solubility by small ubiquitin-like modifier (SUMO). J Biol Chem (2011) 286:18731-46. doi:10.1074/jbc.M111.235978
110. Begitt A, Droescher M, Meyer T, Schmid CD, Baker 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.2794
111. Bluyssen HA, Muzaffar R, Vlieststra RJ, van der Made AC, Leung S, Stark GR, et al. Combinatorial association and abundance of components of interferon-stimulated gene factor 3 dictate the selectivity of interferon responses. Proc Natl Acad Sci U S A (1995) 92:5645-9. doi:10.1073/pnas.92.12.5645
112. Majumder S, Zhou LZ, Chaturvedi P, Babcock G, Aras S, Ransohoff RM. p48/STAT-1alpha-containing complexes play a predominant role in induction of IFN-gamma-inducible protein, 10 kDa (IP-10) by IFN-gamma alone or in synergy with TNF-alpha. J Immunol (1998) 161:4736-44.
113. Rauch I, Rosebrock F, Hainzl E, Heider S, Majoros A, Wienerroither S, et al. Noncanonical effects of IRF9 in intestinal inflammation: more than type I and type III interferons. Mol Cell Biol (2015) 35:2332-43. doi:10.1128/MCB.01498-14
114. Park C, Li S, Cha E, Schindler C. Immune response in Stat2 knockout mice. Immunity (2000) 13:795-804. doi:10.1016/S1074-7613(00)00077-7
115. Matsumoto M, Tanaka N, Harada H, Kimura T, Yokochi T, Kitagawa M, et al. Activation of the transcription factor ISGF3 by interferon-gamma. Biol Chem (1999) 380:699-703. doi:10.1515/BC.1999.087
116. Zimmermann A, Trilling M, Wagner M, Wilborn M, Bubic I, Jonjic S, et al. Cytomegaloviral protein reveals a dual role for STAT2 in IFN-(gamma) signaling and antiviral responses. J Exp Med (2005) 201:1543-53. doi:10.1084/jem.20041401
117. 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.1001359
118. Ho J, Pelzel C, Begitt A, Mee M, Elsheikha HM, Scott DJ, et al. STAT2 is a pervasive cytokine regulator due to its inhibition of STAT1 in multiple signaling pathways. PLoS Biol (2016) 14:e2000117. doi:10.1371/journal.pbio.2000117
119. Bourke LT, Knight RA, Latchman DS, Stephanou A, McCormick J. Signal transducer and activator of transcription-1 localizes to the mitochondria and modulates mitophagy. JAKSTAT (2013) 2:e25666. doi:10.4161/jkst.25666
120. Sisler JD, Morgan M, Raje V, Grande RC, Derecka M, Meier J, et al. The signal transducer and activator of transcription 1 (STAT1) inhibits mitochondrial biogenesis in liver and fatty acid oxidation in adipocytes. PLoS One (2015) 10:e0144444. doi:10.1371/journal.pone.0144444
121. Shahni R, Cale CM, Anderson G, Osellame LD, Hambleton S, Jacques TS, et al. Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission. Brain (2015) 138:2834-46. doi:10.1093/brain/awv182
122. Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE. Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science (2009) 324:1713-6. doi:10.1126/science.1171721
123. Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, et al. Function of mitochondrial Stat3 in cellular respiration. Science (2009) 323:793-7. doi:10.1126/science.1164551
124. Szczepanek K, Lesnefsky EJ, Larner AC. Multi-tasking: nuclear transcription factors with novel roles in the mitochondria. Trends Cell Biol (2012) 22:429-37. doi:10.1016/j.tcb.2012.05.001
125. Sehgal PB. Non-genomic STAT5-dependent effects at the endoplasmic reticulum and Golgi apparatus and STAT6-GFP in mitochondria. JAKSTAT (2013) 2(4):e24860. doi:10.4161/jkst.24860
126. Lee JE, Yang Y-M, Liang F-X, Gough DJ, Levy DE, Sehgal PB. Nongenomic STAT5-dependent effects on Golgi apparatus and endoplasmic reticulum structure and function. Am J Physiol Cell Physiol (2012) 302:C804-20. doi:10.1152/ajpcell.00379.2011
127. Kumar A, Commane M, Flickinger TW, Horvath CM, Stark GR. Defective TNF-alpha-induced apoptosis in STAT1-null cells due to low constitutive levels of caspases. Science (1997) 278:1630-2. doi:10.1126/science.278.5343.1630
128. Putz EM, Majoros A, Gotthardt D, Prchal-Murphy M, Zebedin-Brandl EM, Fux DA, et al. Novel non-canonical role of STAT1 in natural killer cell cytotoxicity. Oncoimmunology (2016) 5:e1186314. doi:10.1080/2162402X.2016.1186314
129. Wen Z, Zhong Z, Darnell JEJ. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell (1995) 82:241-50. doi:10.1016/0092-8674(95)90311-9
130. Kovarik P, Stoiber D, Eyers PA, Menghini R, Neininger A, Gaestel M, et al. Stress-induced phosphorylation of STAT1 at Ser727 requires p38 mitogen-activated protein kinase whereas IFN-gamma uses a different signaling pathway. Proc Natl Acad Sci U S A (1999) 96:13956-61. doi:10.1073/pnas.96.24.13956
131. Bancerek J, Poss ZC, Steinparzer I, Sedlyarov V, Pfaffenwimmer T, Mikulic I, et al. CDK8 kinase phosphorylates transcription factor STAT1 to selectively regulate the interferon response. Immunity (2013) 38:250-62. doi:10.1016/j.immuni.2012.10.017
132. Putz EM, Gotthardt D, Hoermann G, Csiszar A, Wirth S, Berger A, et al. CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance. Cell Rep (2013) 4:437-44. doi:10.1016/j.celrep.2013.07.012
133. Decker T. Emancipation from transcriptional latency: unphosphorylated STAT5 as guardian of hematopoietic differentiation. EMBO J (2016) 35(6):555-7. doi:10.15252/embj.201693974
134. Brown S, Zeidler MP. Unphosphorylated STATs go nuclear. Curr Opin Genet Dev (2008) 18:455-60. doi:10.1016/j.gde.2008.09.002
135. Shi S, Larson K, Guo D, Lim SJ, Dutta P, Yan SJ, et al. Drosophila STAT is required for directly maintaining HP1 localization and heterochromatin stability. Nat Cell Biol (2008) 10:489-96. doi:10.1038/ncb1713
136. Hu X, Dutta P, Tsurumi A, Li J, Wang J, Land H, et al. Unphosphorylated STAT5A stabilizes heterochromatin and suppresses tumor growth. Proc Natl Acad Sci U S A (2013) 110:10213-8. doi:10.1073/pnas.1221243110
137. Park HJ, Li J, Hannah R, Biddie S, Leal-Cervantes AI, Kirschner K, et al. Cytokine-induced megakaryocytic differentiation is regulated by genome-wide loss of a uSTAT transcriptional program. EMBO J (2015) 35:580-94. doi:10.15252/embj.201592383
138. Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev (2007) 21:1396-408. doi:10.1101/gad.1553707
139. Cui X, Zhang L, Luo J, Rajasekaran A, Hazra S, Cacalano N, et al. Unphosphorylated STAT6 contributes to constitutive cyclooxygenase-2 expression in human non-small cell lung cancer. Oncogene (2007) 26:4253-60. doi:10.1038/sj.onc.1210222
140. Reich NC, Liu L. Tracking STAT nuclear traffic. Nat Rev Immunol (2006) 6:602-12. doi:10.1038/nri1885
141. Chatterjee-Kishore M, Wright KL, Ting JP, Stark GR. How Stat1 mediates constitutive gene expression: a complex of unphosphorylated Stat1 and IRF1 supports transcription of the LMP2 gene. EMBO J (2000) 19:4111-22. doi:10.1093/emboj/19.15.4111
142. Meyer T, Gavenis K, Vinkemeier U. Cell type-specific and tyrosine phosphorylation-independent nuclear presence of STAT1 and STAT3. Exp Cell Res (2002) 272:45-55. doi:10.1006/excr.2001.5405
143. Marg A, Shan Y, Meyer T, Meissner T, Brandenburg M, Vinkemeier U. Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and CRM1-dependent nuclear export control the subcellular distribution of latent Stat1. J Cell Biol (2004) 165:823-33. doi:10.1083/jcb.200403057
144. Cheon H, Stark GR. Unphosphorylated STAT1 prolongs the expression of interferon-induced immune regulatory genes. Proc Natl Acad Sci U S A (2009) 106:9373-8. doi:10.1073/pnas.0903487106
145. Cheon H, Holvey-Bates EG, Schoggins JW, Forster S, Hertzog P, Imanaka N, et al. IFNβ-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. EMBO J (2013) 32:2751-63. doi:10.1038/emboj.2013.203
146. Gough DJ, Messina NL, Clarke CJP, Johnstone RW, Levy DE. Constitutive type I interferon modulates homeostatic balance through tonic signaling. Immunity (2012) 36:166-74. doi:10.1016/j.immuni.2012.01.011
147. Suprunenko T, Hofer MJ. The emerging role of interferon regulatory factor 9 in the antiviral host response and beyond. Cytokine Growth Factor Rev (2016) 29:35-43. doi:10.1016/j.cytogfr.2016.03.002
148. Luker KE, Pica CM, Schreiber RD, Piwnica-Worms D. Overexpression of IRF9 confers resistance to antimicrotubule agents in breast cancer cells. Cancer Res (2001) 61:6540-7.
149. Erb HH, Langlechner RV, Moser PL, Handle F, Casneuf T, Verstraeten K, et al. IL6 sensitizes prostate cancer to the antiproliferative effect of IFNa2 through IRF9. Endocr Relat Cancer (2013) 20:677-89. doi:10.1530/ERC-13-0222
150. Hotamisligil GS. Inflammation and metabolic disorders. Nature (2006) 444:860-7. doi:10.1038/nature05485
151. Eguchi J, Yan Q-W, Schones DE, Kamal M, Hsu C-H, Zhang MQ, et al. Interferon regulatory factors are transcriptional regulators of adipogenesis. Cell Metab (2008) 7:86-94. doi:10.1016/j.cmet.2007.11.002
152. Wang X-A, Zhang R, Zhang S, Deng S, Jiang D, Zhong J, et al. Interferon regulatory factor 7 deficiency prevents diet-induced obesity and insulin resistance. Am J Physiol Endocrinol Metab (2013) 305:E485-95. doi:10.1152/ajpendo.00505.2012
153. Wang X-A, Zhang R, She Z-G, Zhang X-F, Jiang D-S, Wang T, et al. Interferon regulatory factor 3 constrains IKKβ/NF-κB signaling to alleviate hepatic steatosis and insulin resistance. Hepatology (2014) 59:870-85. doi:10.1002/hep.26751
154. Wang X-A, Zhang R, Jiang D, Deng W, Zhang S, Deng S, et al. Interferon regulatory factor 9 protects against hepatic insulin resistance and steatosis in male mice. Hepatology (2013) 58:603-16. doi:10.1002/hep.26368
155. Lu J, Bian Z-Y, Zhang R, Zhang Y, Liu C, Yan L, et al. Interferon regulatory factor 3 is a negative regulator of pathological cardiac hypertrophy. Basic Res Cardiol (2013) 108:326. doi:10.1007/s00395-012-0326-9
156. Jiang D-S, Liu Y, Zhou H, Zhang Y, Zhang X-D, Zhang X-F, et al. Interferon regulatory factor 7 functions as a novel negative regulator of pathological cardiac hypertrophy. Hypertension (2014) 63:713-22. doi:10.1161/HYPERTENSIONAHA.113.02653
157. Jiang D-S, Luo Y-X, Zhang R, Zhang X-D, Chen H-Z, Zhang Y, et al. Interferon regulatory factor 9 protects against cardiac hypertrophy by targeting myocardin. Hypertension (2014) 63:119-27. doi:10.1161/HYPERTENSIONAHA.113.02083
158. Zhang X, Bogunovic D, Payelle-Brogard B, Francois-Newton V, Speer SD, Yuan C, et al. Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation. Nature (2014) 517:89-93. doi:10.1038/nature13801
159. Chen H-Z, Guo S, Li Z-Z, Lu Y, Jiang D-S, Zhang R, et al. A critical role for interferon regulatory factor 9 in cerebral ischemic stroke. J Neurosci (2014) 34:11897-912. doi:10.1523/JNEUROSCI.1545-14.2014
160. Zhang S-M, Zhu L-H, Chen H-Z, Zhang R, Zhang P, Jiang D-S, et al. Interferon regulatory factor 9 is critical for neointima formation following vascular injury. Nat Commun (2014) 5:5160. doi:10.1038/ncomms6160162
161. Kawata T. STAT signaling in Dictyostelium development. Dev Growth Differ (2011) 53:548-57. doi:10.1111/j.1440-169X.2010.01243.x