Pre-assembly of STAT4 with the Human IFN-alpha/beta Receptor-2 Subunit is Mediated by the STAT4 N-domain

Overview

Journal Mol Immunol

Specialties Allergy & Immunology
Molecular Biology

Date 2006 Nov 11

PMID 17095088

Citations 17

Authors

Douglas R Tyler

Meredith E Persky

Loderick A Matthews

Sheuwen Chan

J David Farrar

Affiliations

Soon will be listed here.

Abstract

CD4(+) T cells regulate adaptive responses to pathogens by secreting unique subsets of cytokines that mediate inflammatory processes. The innate cytokines IL-12 and IFN-alpha/beta regulate type I responses and promote acute IFN-gamma secretion through the activation of the STAT4 transcription factor. Although IL-12-induced STAT4 activation is a conserved pathway across species, IFN-alpha/beta-dependent STAT4 phosphorylation does not occur as efficiently in mice as it does in human T cells. In order to understand this species-specific pathway for IFN-alpha/beta-dependent STAT4 activation, we have examined the molecular basis of STAT4 recruitment by the human IFNAR. In this report, we demonstrate that the N-domain of STAT4 interacts with the cytoplasmic domain of the human, but not the murine IFNAR2 subunit. This interaction mapped to a membrane-proximal segment of the hIFNAR2 spanning amino acids 299-333. Deletion of this region within the hIFNAR2 completely abolishes IFN-alpha/beta-dependent STAT4 tyrosine phosphorylation when expressed in human IFNAR2-deficient fibroblasts. Thus, the human IFNAR2 cytoplasmic domain serves to link STAT4 to the IFNAR as a pre-assembled complex that facilitates cytokine-driven STAT4 activation.

Citing Articles

Genetic polymorphisms in genes involved in the type I interferon system (STAT4 and IRF5): association with Asian SLE patients.

Liu M, Wang S, Liang Y, Fan Y, Wang W Clin Rheumatol. 2024; 43(8):2403-2416.

PMID: 38963465 DOI: 10.1007/s10067-024-07046-8.

Renin Promotes STAT4 Phosphorylation to Induce IL-17 Production in Keratinocytes of Oral Lichen Planus.

Ge X, Xie H, Nguyen T, Zhao B, Xu J, Du J iScience. 2020; 23(4):100983.

PMID: 32213463 PMC: 7093809. DOI: 10.1016/j.isci.2020.100983.

The diagnosis values of serum STAT4 and sEng in preeclampsia.

Zhang L, Li X, Zhou C, You Z, Zhang J, Cao G J Clin Lab Anal. 2019; 34(2):e23073.

PMID: 31628681 PMC: 7031581. DOI: 10.1002/jcla.23073.

The molecular basis for differential type I interferon signaling.

Schreiber G J Biol Chem. 2017; 292(18):7285-7294.

PMID: 28289098 PMC: 5418031. DOI: 10.1074/jbc.R116.774562.

Autocrine Loop Involving IL-6 Family Member LIF, LIF Receptor, and STAT4 Drives Sustained Fibroblast Production of Inflammatory Mediators.

Nguyen H, Noss E, Mizoguchi F, Huppertz C, Wei K, Watts G Immunity. 2017; 46(2):220-232.

PMID: 28228280 PMC: 5567864. DOI: 10.1016/j.immuni.2017.01.004.

References

Park C, Lecomte M, Schindler C . Murine Stat2 is uncharacteristically divergent. Nucleic Acids Res. 1999; 27(21):4191-9. PMC: 148693. DOI: 10.1093/nar/27.21.4191. View

Persky M, Murphy K, Farrar J . IL-12, but not IFN-alpha, promotes STAT4 activation and Th1 development in murine CD4+ T cells expressing a chimeric murine/human Stat2 gene. J Immunol. 2004; 174(1):294-301. DOI: 10.4049/jimmunol.174.1.294. View

PAULSON M, Pisharody S, Pan L, Guadagno S, Mui A, Levy D . Stat protein transactivation domains recruit p300/CBP through widely divergent sequences. J Biol Chem. 1999; 274(36):25343-9. DOI: 10.1074/jbc.274.36.25343. View

Sinigaglia F, DAmbrosio D, Rogge L . Type I interferons and the Th1/Th2 paradigm. Dev Comp Immunol. 1999; 23(7-8):657-63. DOI: 10.1016/s0145-305x(99)00039-7. View

Farrar J, Smith J, MURPHY T, Murphy K . Recruitment of Stat4 to the human interferon-alpha/beta receptor requires activated Stat2. J Biol Chem. 2000; 275(4):2693-7. DOI: 10.1074/jbc.275.4.2693. View

Sareneva T, Julkunen I, Matikainen S . IFN-alpha and IL-12 induce IL-18 receptor gene expression in human NK and T cells. J Immunol. 2000; 165(4):1933-8. DOI: 10.4049/jimmunol.165.4.1933. View

MURPHY T, Geissal E, Farrar J, Murphy K . Role of the Stat4 N domain in receptor proximal tyrosine phosphorylation. Mol Cell Biol. 2000; 20(19):7121-31. PMC: 86263. DOI: 10.1128/MCB.20.19.7121-7131.2000. View

Farrar J, Murphy K . Type I interferons and T helper development. Immunol Today. 2000; 21(10):484-9. DOI: 10.1016/s0167-5699(00)01710-2. View

Farrar J, Smith J, MURPHY T, Leung S, Stark G, Murphy K . Selective loss of type I interferon-induced STAT4 activation caused by a minisatellite insertion in mouse Stat2. Nat Immunol. 2001; 1(1):65-9. DOI: 10.1038/76932. View

10.

Matikainen S, Paananen A, Miettinen M, Kurimoto M, Timonen T, Julkunen I . IFN-alpha and IL-18 synergistically enhance IFN-gamma production in human NK cells: differential regulation of Stat4 activation and IFN-gamma gene expression by IFN-alpha and IL-12. Eur J Immunol. 2001; 31(7):2236-45. View

11.

Chen X, Bhandari R, Vinkemeier U, van den Akker F, Darnell Jr J, Kuriyan J . A reinterpretation of the dimerization interface of the N-terminal domains of STATs. Protein Sci. 2003; 12(2):361-5. PMC: 2312425. DOI: 10.1110/ps.0218903. View

12.

Trinchieri G . Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nat Rev Immunol. 2003; 3(2):133-46. DOI: 10.1038/nri1001. View

13.

Szabo S, Sullivan B, Peng S, Glimcher L . Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol. 2002; 21:713-58. DOI: 10.1146/annurev.immunol.21.120601.140942. View

14.

Wiederkehr-Adam M, Ernst P, Muller K, Bieck E, Gombert F, Ottl J . Characterization of phosphopeptide motifs specific for the Src homology 2 domains of signal transducer and activator of transcription 1 (STAT1) and STAT3. J Biol Chem. 2003; 278(18):16117-28. DOI: 10.1074/jbc.M300261200. View

15.

Chang H, Zhang S, Oldham I, Naeger L, Hoey T, Kaplan M . STAT4 requires the N-terminal domain for efficient phosphorylation. J Biol Chem. 2003; 278(34):32471-7. DOI: 10.1074/jbc.M302776200. View

16.

Ota N, Brett T, Murphy T, Fremont D, Murphy K . N-domain-dependent nonphosphorylated STAT4 dimers required for cytokine-driven activation. Nat Immunol. 2004; 5(2):208-15. DOI: 10.1038/ni1032. View

17.

Berenson L, Farrar J, Murphy T, Murphy K . Frontline: absence of functional STAT4 activation despite detectable tyrosine phosphorylation induced by murine IFN-alpha. Eur J Immunol. 2004; 34(9):2365-74. DOI: 10.1002/eji.200324829. View

18.

Parronchi P, De Carli M, Manetti R, Simonelli C, Sampognaro S, Piccinni M . IL-4 and IFN (alpha and gamma) exert opposite regulatory effects on the development of cytolytic potential by Th1 or Th2 human T cell clones. J Immunol. 1992; 149(9):2977-83. View

19.

Brinkmann V, Geiger T, Alkan S, Heusser C . Interferon alpha increases the frequency of interferon gamma-producing human CD4+ T cells. J Exp Med. 1993; 178(5):1655-63. PMC: 2191249. DOI: 10.1084/jem.178.5.1655. View

20.

Heim M, Kerr I, Stark G, Darnell Jr J . Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway. Science. 1995; 267(5202):1347-9. DOI: 10.1126/science.7871432. View