Multifarious Determinants of Cytokine Receptor Signaling Specificity

Overview

Journal Adv Immunol

Specialty Allergy & Immunology

Date 2014 Jan 7

PMID 24388212

Citations 37

Authors

Ignacio Moraga

Jamie Spangler

Juan L Mendoza

K Christopher Garcia

Affiliations

Soon will be listed here.

Abstract

Cytokines play crucial roles in regulating immune homeostasis. Two important characteristics of most cytokines are pleiotropy, defined as the ability of one cytokine to exhibit diverse functionalities, and redundancy, defined as the ability of multiple cytokines to exert overlapping activities. Identifying the determinants for unique cellular responses to cytokines in the face of shared receptor usage, pleiotropy, and redundancy will be essential in order to harness the potential of cytokines as therapeutics. Here, we discuss the biophysical (ligand-receptor geometry and affinity) and cellular (receptor trafficking and intracellular abundance of signaling molecules) parameters that contribute to the specificity of cytokine bioactivities. Whereas the role of extracellular ternary complex geometry in cytokine-induced signaling is still not completely elucidated, cytokine-receptor affinity is known to impact signaling through modulation of the stability and kinetics of ternary complex formation. Receptor trafficking also plays an important and likely underappreciated role in the diversification of cytokine bioactivities but it has been challenging to experimentally probe trafficking effects. We also review recent efforts to quantify levels of intracellular signaling components, as second messenger abundance can affect cytokine-induced bioactivities both quantitatively and qualitatively. We conclude by discussing the application of protein engineering to develop therapeutically relevant cytokines with reduced pleiotropy and redirected biological functionalities.

Citing Articles

Non-contact immunological signaling for highly-efficient regulation of the transcriptional map of human monocytes.

Hashoul D, Saliba W, Broza Y, Haick H Bioeng Transl Med. 2024; 9(3):e10519.

PMID: 38818125 PMC: 11135151. DOI: 10.1002/btm2.10519.

Aqueous Macrophages Contribute to Conserved CCL2 and CXCL10 Gradients in Uveitis.

Lin J, Pepple K, Concepcion C, Korshunova Y, Paley M, Paley G Ophthalmol Sci. 2024; 4(4):100453.

PMID: 38650614 PMC: 11033188. DOI: 10.1016/j.xops.2023.100453.

Navigating the Cytokine Seas: Targeting Cytokine Signaling Pathways in Cancer Therapy.

Stanilov N, Velikova T, Stanilova S Int J Mol Sci. 2024; 25(2).

PMID: 38256080 PMC: 10815616. DOI: 10.3390/ijms25021009.

Distinct Assemblies of Heterodimeric Cytokine Receptors Govern Stemness Programs in Leukemia.

Kan W, Dhagat U, Kaufmann K, Hercus T, Nero T, Zeng A Cancer Discov. 2023; 13(8):1922-1947.

PMID: 37191437 PMC: 10401075. DOI: 10.1158/2159-8290.CD-22-1396.

A peptide derived from HSP60 reduces proinflammatory cytokines and soluble mediators: a therapeutic approach to inflammation.

Dominguez-Horta M, Serrano-Diaz A, Hernandez-Cedeno M, Martinez-Donato G, Guillen-Nieto G Front Immunol. 2023; 14:1162739.

PMID: 37187739 PMC: 10179499. DOI: 10.3389/fimmu.2023.1162739.

References

Zhu J, Guo L, Watson C, Hu-Li J, Paul W . Stat6 is necessary and sufficient for IL-4's role in Th2 differentiation and cell expansion. J Immunol. 2001; 166(12):7276-81. DOI: 10.4049/jimmunol.166.12.7276. View

Jones B, Logsdon N, Walter M . Structure of IL-22 bound to its high-affinity IL-22R1 chain. Structure. 2008; 16(9):1333-44. PMC: 2637415. DOI: 10.1016/j.str.2008.06.005. View

Fuh G, Colosi P, Wood W, Wells J . Mechanism-based design of prolactin receptor antagonists. J Biol Chem. 1993; 268(8):5376-81. View

Junttila I, Creusot R, Moraga I, Bates D, Wong M, Alonso M . Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines. Nat Chem Biol. 2012; 8(12):990-8. PMC: 3508151. DOI: 10.1038/nchembio.1096. View

Schoggins J, Wilson S, Panis M, Murphy M, Jones C, Bieniasz P . A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011; 472(7344):481-5. PMC: 3409588. DOI: 10.1038/nature09907. View

Andrews A, Holloway J, Holgate S, Davies D . IL-4 receptor alpha is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets. J Immunol. 2006; 176(12):7456-61. DOI: 10.4049/jimmunol.176.12.7456. View

Fuh G, Cunningham B, Fukunaga R, Nagata S, Goeddel D, Wells J . Rational design of potent antagonists to the human growth hormone receptor. Science. 1992; 256(5064):1677-80. DOI: 10.1126/science.256.5064.1677. View

Constantinescu S, Huang L, Nam H, Lodish H . The erythropoietin receptor cytosolic juxtamembrane domain contains an essential, precisely oriented, hydrophobic motif. Mol Cell. 2001; 7(2):377-85. DOI: 10.1016/s1097-2765(01)00185-x. View

Pfeffer L, Stebbing N, Donner D . Cytoskeletal association of human alpha-interferon-receptor complexes in interferon-sensitive and -resistant lymphoblastoid cells. Proc Natl Acad Sci U S A. 1987; 84(10):3249-53. PMC: 304846. DOI: 10.1073/pnas.84.10.3249. View

10.

Boulanger M, Bankovich A, Kortemme T, Baker D, Garcia K . Convergent mechanisms for recognition of divergent cytokines by the shared signaling receptor gp130. Mol Cell. 2003; 12(3):577-89. DOI: 10.1016/s1097-2765(03)00365-4. View

11.

Thomas C, Moraga I, Levin D, Krutzik P, Podoplelova Y, Trejo A . Structural linkage between ligand discrimination and receptor activation by type I interferons. Cell. 2011; 146(4):621-32. PMC: 3166218. DOI: 10.1016/j.cell.2011.06.048. View

12.

Watowich S, Yoshimura A, Longmore G, Hilton D, Yoshimura Y, Lodish H . Homodimerization and constitutive activation of the erythropoietin receptor. Proc Natl Acad Sci U S A. 1992; 89(6):2140-4. PMC: 48612. DOI: 10.1073/pnas.89.6.2140. View

13.

Pal G, Kossiakoff A, Sidhu S . The functional binding epitope of a high affinity variant of human growth hormone mapped by shotgun alanine-scanning mutagenesis: insights into the mechanisms responsible for improved affinity. J Mol Biol. 2003; 332(1):195-204. DOI: 10.1016/s0022-2836(03)00898-2. View

14.

Friedrich K, Kammer W, Erhardt I, Brandlein S, Arnold S, Sebald W . The two subunits of the interleukin-4 receptor mediate independent and distinct patterns of ligand endocytosis. Eur J Biochem. 1999; 265(1):457-65. DOI: 10.1046/j.1432-1327.1999.00773.x. View

15.

Ihle J, Witthuhn B, Quelle F, Yamamoto K, Silvennoinen O . Signaling through the hematopoietic cytokine receptors. Annu Rev Immunol. 1995; 13:369-98. DOI: 10.1146/annurev.iy.13.040195.002101. View

16.

Gauzzi M, Barbieri G, Richter M, Uze G, Ling L, Fellous M . The amino-terminal region of Tyk2 sustains the level of interferon alpha receptor 1, a component of the interferon alpha/beta receptor. Proc Natl Acad Sci U S A. 1997; 94(22):11839-44. PMC: 23625. DOI: 10.1073/pnas.94.22.11839. View

17.

David M, Petricoin 3rd E, Benjamin C, Pine R, Weber M, Larner A . Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. Science. 1995; 269(5231):1721-3. DOI: 10.1126/science.7569900. View

18.

Piehler J, Thomas C, Garcia K, Schreiber G . Structural and dynamic determinants of type I interferon receptor assembly and their functional interpretation. Immunol Rev. 2012; 250(1):317-34. PMC: 3986811. DOI: 10.1111/imr.12001. View

19.

Lamken P, Lata S, Gavutis M, Piehler J . Ligand-induced assembling of the type I interferon receptor on supported lipid bilayers. J Mol Biol. 2004; 341(1):303-18. DOI: 10.1016/j.jmb.2004.05.059. View

20.

Livnah O, Stura E, Middleton S, Johnson D, Jolliffe L, Wilson I . Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science. 1999; 283(5404):987-90. DOI: 10.1126/science.283.5404.987. View