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Shared receptor components but distinct complexes for alpha and beta interferons

M Lewerenz1, K E Mogensen, G Uzé

  • 1Institut de Génétique Moléculaire, CNRS UMR 5535, 1919 Route de Mende, Montpellier Cedex 5, 34293, France.

Journal of Molecular Biology
|September 17, 1998
PubMed
Summary
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Alpha and beta interferons signal differently by interacting with their receptor subunits, ifnar1 and ifnar2, in distinct ways. This study reveals unique ligand-receptor interactions for type I interferons.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • Type I interferons (IFNs) encompass alpha, omega, and beta subtypes.
  • These IFNs signal through a receptor complex of interferon alpha/beta receptor subunits 1 and 2 (IFNAR1 and IFNAR2) and Janus tyrosine kinases (Tyk2 and Jak1).
  • Previous studies suggested differential signaling pathways for alpha and beta interferons.

Purpose of the Study:

  • To investigate the distinct signaling mechanisms of alpha and beta interferons through their shared receptor.
  • To elucidate the specific interactions between interferon subtypes and receptor subunits.

Main Methods:

  • Alanine-scanning mutagenesis was performed on the extracellular domain of IFNAR2.
  • Mutant IFNAR2 was expressed in U5A cells lacking endogenous IFNAR2.

Related Experiment Videos

  • A selection strategy identified mutants with altered responses to alpha or beta interferon.
  • Characterization of a specific mutant (TMK) and comparison with wild-type and Tyk2-deficient cells.
  • Utilized anti-receptor antibodies and mutant beta interferon forms to probe ligand-receptor interactions.

    • Main Results:

    • Three groups of mutants were identified based on differential sensitivity to alpha and beta interferons.
    • A TMK mutant showed resistance to alpha interferon and sensitivity to beta interferon.
    • Three distinct ligand-receptor interaction modes were observed: (i) alpha interferon with IFNAR1 and IFNAR2, (ii) beta interferon with IFNAR1 and IFNAR2, and (iii) beta interferon with IFNAR2 alone.

    Conclusions:

    • Alpha and beta interferons exhibit distinct signaling pathways.
    • These differences arise from unique interaction patterns between each interferon subtype and the IFNAR1/IFNAR2 receptor complex.
    • Ligand interaction with IFNAR2 alone represents a novel signaling mode for beta interferon.