Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Jun 6;92(12):5401–5405. doi: 10.1073/pnas.92.12.5401

Interferon gamma signals via a high-affinity multisubunit receptor complex that contains two types of polypeptide chain.

S A Marsters 1, D Pennica 1, E Bach 1, R D Schreiber 1, A Ashkenazi 1
PMCID: PMC41702  PMID: 7777519

Abstract

Signaling by interferon gamma (IFN-gamma) requires two structurally related cell surface proteins: a ligand-binding polypeptide, known as the IFN-gamma receptor (IFN-gamma R), and an accessory factor. However, it is not known whether IFN-gamma forms a ternary complex with the IFN-gamma R and accessory factor to initiate signaling. Here we demonstrate complex formation between IFN-gamma and the two proteins, both in solution and at the cell surface. We observe complexes containing ligand, two molecules of IFN-gamma R (designated the IFN-gamma R alpha chain), and one or two molecules of accessory factor (designated the IFN-gamma R beta chain). Transfected cells expressing both IFN-gamma R chains bind IFN-gamma with higher affinity than do cells expressing alpha chain alone. Anti-beta-chain antibodies prevent the beta chain from participating in the ligand-receptor complex, reduce the affinity for IFN-gamma, and block signaling. Soluble alpha- or beta-chain extracellular domains also inhibit function. These results demonstrate that IFN-gamma signals via a high-affinity multisubunit complex that contains two types of receptor chain and suggest a potential approach to inhibiting specific actions of IFN-gamma by blocking the association of receptor subunits.

Full text

PDF
5401

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aguet M., Dembić Z., Merlin G. Molecular cloning and expression of the human interferon-gamma receptor. Cell. 1988 Oct 21;55(2):273–280. doi: 10.1016/0092-8674(88)90050-5. [DOI] [PubMed] [Google Scholar]
  2. Ashkenazi A., Capon D. J., Ward R. H. Immunoadhesins. Int Rev Immunol. 1993;10(2-3):219–227. doi: 10.3109/08830189309061697. [DOI] [PubMed] [Google Scholar]
  3. Ashkenazi A., Marsters S. A., Capon D. J., Chamow S. M., Figari I. S., Pennica D., Goeddel D. V., Palladino M. A., Smith D. H. Protection against endotoxic shock by a tumor necrosis factor receptor immunoadhesin. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10535–10539. doi: 10.1073/pnas.88.23.10535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Axelrod A., Gibbs V. C., Goeddel D. V. The interferon-gamma receptor extracellular domain. Non-identical requirements for ligand binding and signaling. J Biol Chem. 1994 Jun 3;269(22):15533–15539. [PubMed] [Google Scholar]
  5. Bazan J. F. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A. 1990 Sep;87(18):6934–6938. doi: 10.1073/pnas.87.18.6934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Beck J. T., Marsters S. A., Harris R. J., Carter P., Ashkenazi A., Chamow S. M. Generation of soluble interleukin-1 receptor from an immunoadhesin by specific cleavage. Mol Immunol. 1994 Dec;31(17):1335–1344. doi: 10.1016/0161-5890(94)90052-3. [DOI] [PubMed] [Google Scholar]
  7. Carter P., Nilsson B., Burnier J. P., Burdick D., Wells J. A. Engineering subtilisin BPN' for site-specific proteolysis. Proteins. 1989;6(3):240–248. doi: 10.1002/prot.340060306. [DOI] [PubMed] [Google Scholar]
  8. Darnell J. E., Jr, Kerr I. M., Stark G. R. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994 Jun 3;264(5164):1415–1421. doi: 10.1126/science.8197455. [DOI] [PubMed] [Google Scholar]
  9. Dighe A. S., Farrar M. A., Schreiber R. D. Inhibition of cellular responsiveness to interferon-gamma (IFN gamma) induced by overexpression of inactive forms of the IFN gamma receptor. J Biol Chem. 1993 May 15;268(14):10645–10653. [PubMed] [Google Scholar]
  10. Ealick S. E., Cook W. J., Vijay-Kumar S., Carson M., Nagabhushan T. L., Trotta P. P., Bugg C. E. Three-dimensional structure of recombinant human interferon-gamma. Science. 1991 May 3;252(5006):698–702. doi: 10.1126/science.1902591. [DOI] [PubMed] [Google Scholar]
  11. Evan G. I., Lewis G. K., Ramsay G., Bishop J. M. Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product. Mol Cell Biol. 1985 Dec;5(12):3610–3616. doi: 10.1128/mcb.5.12.3610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Farrar M. A., Schreiber R. D. The molecular cell biology of interferon-gamma and its receptor. Annu Rev Immunol. 1993;11:571–611. doi: 10.1146/annurev.iy.11.040193.003035. [DOI] [PubMed] [Google Scholar]
  13. Fountoulakis M., Zulauf M., Lustig A., Garotta G. Stoichiometry of interaction between interferon gamma and its receptor. Eur J Biochem. 1992 Sep 15;208(3):781–787. doi: 10.1111/j.1432-1033.1992.tb17248.x. [DOI] [PubMed] [Google Scholar]
  14. Gibbs V. C., Williams S. R., Gray P. W., Schreiber R. D., Pennica D., Rice G., Goeddel D. V. The extracellular domain of the human interferon gamma receptor interacts with a species-specific signal transducer. Mol Cell Biol. 1991 Dec;11(12):5860–5866. doi: 10.1128/mcb.11.12.5860. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Greenlund A. C., Farrar M. A., Viviano B. L., Schreiber R. D. Ligand-induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91). EMBO J. 1994 Apr 1;13(7):1591–1600. doi: 10.1002/j.1460-2075.1994.tb06422.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Greenlund A. C., Schreiber R. D., Goeddel D. V., Pennica D. Interferon-gamma induces receptor dimerization in solution and on cells. J Biol Chem. 1993 Aug 25;268(24):18103–18110. [PubMed] [Google Scholar]
  17. Haak-Frendscho M., Marsters S. A., Chamow S. M., Peers D. H., Simpson N. J., Ashkenazi A. Inhibition of interferon-gamma by an interferon-gamma receptor immunoadhesin. Immunology. 1993 Aug;79(4):594–599. [PMC free article] [PubMed] [Google Scholar]
  18. Hemmi S., Böhni R., Stark G., Di Marco F., Aguet M. A novel member of the interferon receptor family complements functionality of the murine interferon gamma receptor in human cells. Cell. 1994 Mar 11;76(5):803–810. doi: 10.1016/0092-8674(94)90355-7. [DOI] [PubMed] [Google Scholar]
  19. Hemmi S., Merlin G., Aguet M. Functional characterization of a hybrid human-mouse interferon gamma receptor: evidence for species-specific interaction of the extracellular receptor domain with a putative signal transducer. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2737–2741. doi: 10.1073/pnas.89.7.2737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hibino Y., Kumar C. S., Mariano T. M., Lai D. H., Pestka S. Chimeric interferon-gamma receptors demonstrate that an accessory factor required for activity interacts with the extracellular domain. J Biol Chem. 1992 Feb 25;267(6):3741–3749. [PubMed] [Google Scholar]
  21. Ho A. S., Liu Y., Khan T. A., Hsu D. H., Bazan J. F., Moore K. W. A receptor for interleukin 10 is related to interferon receptors. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11267–11271. doi: 10.1073/pnas.90.23.11267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Igarashi K., Garotta G., Ozmen L., Ziemiecki A., Wilks A. F., Harpur A. G., Larner A. C., Finbloom D. S. Interferon-gamma induces tyrosine phosphorylation of interferon-gamma receptor and regulated association of protein tyrosine kinases, Jak1 and Jak2, with its receptor. J Biol Chem. 1994 May 20;269(20):14333–14336. [PubMed] [Google Scholar]
  23. Kishimoto T., Taga T., Akira S. Cytokine signal transduction. Cell. 1994 Jan 28;76(2):253–262. doi: 10.1016/0092-8674(94)90333-6. [DOI] [PubMed] [Google Scholar]
  24. Kürschner C., Garotta G., Dembić Z. Construction, purification, and characterization of new interferon gamma (IFN gamma) inhibitor proteins. Three IFN gamma receptor-immunoglobulin hybrid molecules. J Biol Chem. 1992 May 5;267(13):9354–9360. [PubMed] [Google Scholar]
  25. Laegreid A., Medvedev A., Nonstad U., Bombara M. P., Ranges G., Sundan A., Espevik T. Tumor necrosis factor receptor p75 mediates cell-specific activation of nuclear factor kappa B and induction of human cytomegalovirus enhancer. J Biol Chem. 1994 Mar 11;269(10):7785–7791. [PubMed] [Google Scholar]
  26. Lutfalla G., Gardiner K., Uzé G. A new member of the cytokine receptor gene family maps on chromosome 21 at less than 35 kb from IFNAR. Genomics. 1993 May;16(2):366–373. doi: 10.1006/geno.1993.1199. [DOI] [PubMed] [Google Scholar]
  27. Morrissey J. H., Fakhrai H., Edgington T. S. Molecular cloning of the cDNA for tissue factor, the cellular receptor for the initiation of the coagulation protease cascade. Cell. 1987 Jul 3;50(1):129–135. doi: 10.1016/0092-8674(87)90669-6. [DOI] [PubMed] [Google Scholar]
  28. Müller M., Briscoe J., Laxton C., Guschin D., Ziemiecki A., Silvennoinen O., Harpur A. G., Barbieri G., Witthuhn B. A., Schindler C. The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction. Nature. 1993 Nov 11;366(6451):129–135. doi: 10.1038/366129a0. [DOI] [PubMed] [Google Scholar]
  29. Novick D., Cohen B., Rubinstein M. The human interferon alpha/beta receptor: characterization and molecular cloning. Cell. 1994 May 6;77(3):391–400. doi: 10.1016/0092-8674(94)90154-6. [DOI] [PubMed] [Google Scholar]
  30. Pearse R. N., Feinman R., Shuai K., Darnell J. E., Jr, Ravetch J. V. Interferon gamma-induced transcription of the high-affinity Fc receptor for IgG requires assembly of a complex that includes the 91-kDa subunit of transcription factor ISGF3. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4314–4318. doi: 10.1073/pnas.90.9.4314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rashidbaigi A., Langer J. A., Jung V., Jones C., Morse H. G., Tischfield J. A., Trill J. J., Kung H. F., Pestka S. The gene for the human immune interferon receptor is located on chromosome 6. Proc Natl Acad Sci U S A. 1986 Jan;83(2):384–388. doi: 10.1073/pnas.83.2.384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Smith D. H., Byrn R. A., Marsters S. A., Gregory T., Groopman J. E., Capon D. J. Blocking of HIV-1 infectivity by a soluble, secreted form of the CD4 antigen. Science. 1987 Dec 18;238(4834):1704–1707. doi: 10.1126/science.3500514. [DOI] [PubMed] [Google Scholar]
  33. Soh J., Donnelly R. J., Kotenko S., Mariano T. M., Cook J. R., Wang N., Emanuel S., Schwartz B., Miki T., Pestka S. Identification and sequence of an accessory factor required for activation of the human interferon gamma receptor. Cell. 1994 Mar 11;76(5):793–802. doi: 10.1016/0092-8674(94)90354-9. [DOI] [PubMed] [Google Scholar]
  34. Uzé G., Lutfalla G., Gresser I. Genetic transfer of a functional human interferon alpha receptor into mouse cells: cloning and expression of its cDNA. Cell. 1990 Jan 26;60(2):225–234. doi: 10.1016/0092-8674(90)90738-z. [DOI] [PubMed] [Google Scholar]
  35. Watling D., Guschin D., Müller M., Silvennoinen O., Witthuhn B. A., Quelle F. W., Rogers N. C., Schindler C., Stark G. R., Ihle J. N. Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway. Nature. 1993 Nov 11;366(6451):166–170. doi: 10.1038/366166a0. [DOI] [PubMed] [Google Scholar]
  36. Wilson K. C., Finbloom D. S. Interferon gamma rapidly induces in human monocytes a DNA-binding factor that recognizes the gamma response region within the promoter of the gene for the high-affinity Fc gamma receptor. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11964–11968. doi: 10.1073/pnas.89.24.11964. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES