title: Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling.
abstract: Type I interferons (IFNs) activate differential cellular responses through a shared cell surface receptor composed of the two subunits, IFNAR1 and IFNAR2. We propose here a mechanistic model for how IFN receptor plasticity is regulated on the level of receptor dimerization. Quantitative single-molecule imaging of receptor assembly in the plasma membrane of living cells clearly identified IFN-induced dimerization of IFNAR1 and IFNAR2. The negative feedback regulator ubiquitin-specific protease 18 (USP18) potently interferes with the recruitment of IFNAR1 into the ternary complex, probably by impeding complex stabilization related to the associated Janus kinases. Thus, the responsiveness to IFNα2 is potently down-regulated after the first wave of gene induction, while IFNβ, due to its ∼100-fold higher binding affinity, is still able to efficiently recruit IFNAR1. Consistent with functional data, this novel regulatory mechanism at the level of receptor assembly explains how signaling by IFNβ is maintained over longer times compared with IFNα2 as a temporally encoded cause of functional receptor plasticity.
authors.affiliation: Department of Biology, Division of Biophysics, University of Osnabrück, 49074 Osnabrück, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wilmes
authors.affiliation: Department of Biology, Division of Biophysics, University of Osnabrück, 49074 Osnabrück, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Beutel
authors.affiliation: Institut Pasteur, Cytokine Signaling Unit, Centre National de la Recherche Scientifique URA1961, 75724 Paris, France.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institut Pasteur, Cytokine Signaling Unit, Centre National de la Recherche Scientifique URA1961, 75724 Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Francois-Newton
authors.affiliation: Department of Biology, Division of Biophysics, University of Osnabrück, 49074 Osnabrück, Germany.
authors.forename: Christian P
authors.initials: CP
authors.lastname: Richter
authors.affiliation: Department of Biology, Division of Biophysics, University of Osnabrück, 49074 Osnabrück, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Janning
authors.affiliation: Department of Biology, Division of Biophysics, University of Osnabrück, 49074 Osnabrück, Germany.
authors.forename: Cindy
authors.initials: C
authors.lastname: Kroll
authors.affiliation: Department of Biology, Division of Biophysics, University of Osnabrück, 49074 Osnabrück, Germany.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Hanhart
authors.affiliation: Department of Biology, Division of Biophysics, University of Osnabrück, 49074 Osnabrück, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Hötte
authors.affiliation: Department of Biology, Division of Biophysics, University of Osnabrück, 49074 Osnabrück, Germany.
authors.forename: Changjiang
authors.initials: C
authors.lastname: You
authors.affiliation: Centre National de la Recherche Scientifique Montpellier, 34095 Montpellier, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Uzé
authors.affiliation: Institut Pasteur, Cytokine Signaling Unit, Centre National de la Recherche Scientifique URA1961, 75724 Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pellegrini
authors.affiliation: Department of Biology, Division of Biophysics, University of Osnabrück, 49074 Osnabrück, Germany piehler@uos.de.
authors.forename: Jacob
authors.initials: J
authors.lastname: Piehler
mesh_terms: D010450:Endopeptidases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D053613:Janus Kinase 1 / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D055550:Protein Stability; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D015398:Signal Transduction; D043222:Ubiquitin Thiolesterase
chemical_list: C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase