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Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling

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-molec...

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Autores principales: Wilmes, Stephan, Beutel, Oliver, Li, Zhi, Francois-Newton, Véronique, Richter, Christian P., Janning, Dennis, Kroll, Cindy, Hanhart, Patrizia, Hötte, Katharina, You, Changjiang, Uzé, Gilles, Pellegrini, Sandra, Piehler, Jacob
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442803/
https://www.ncbi.nlm.nih.gov/pubmed/26008745
http://dx.doi.org/10.1083/jcb.201412049
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author Wilmes, Stephan
Beutel, Oliver
Li, Zhi
Francois-Newton, Véronique
Richter, Christian P.
Janning, Dennis
Kroll, Cindy
Hanhart, Patrizia
Hötte, Katharina
You, Changjiang
Uzé, Gilles
Pellegrini, Sandra
Piehler, Jacob
author_facet Wilmes, Stephan
Beutel, Oliver
Li, Zhi
Francois-Newton, Véronique
Richter, Christian P.
Janning, Dennis
Kroll, Cindy
Hanhart, Patrizia
Hötte, Katharina
You, Changjiang
Uzé, Gilles
Pellegrini, Sandra
Piehler, Jacob
author_sort Wilmes, Stephan
collection PubMed
description 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.
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spelling pubmed-44428032015-11-25 Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling Wilmes, Stephan Beutel, Oliver Li, Zhi Francois-Newton, Véronique Richter, Christian P. Janning, Dennis Kroll, Cindy Hanhart, Patrizia Hötte, Katharina You, Changjiang Uzé, Gilles Pellegrini, Sandra Piehler, Jacob J Cell Biol Research Articles 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. The Rockefeller University Press 2015-05-25 /pmc/articles/PMC4442803/ /pubmed/26008745 http://dx.doi.org/10.1083/jcb.201412049 Text en © 2015 Wilmes et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Wilmes, Stephan
Beutel, Oliver
Li, Zhi
Francois-Newton, Véronique
Richter, Christian P.
Janning, Dennis
Kroll, Cindy
Hanhart, Patrizia
Hötte, Katharina
You, Changjiang
Uzé, Gilles
Pellegrini, Sandra
Piehler, Jacob
Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling
title Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling
title_full Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling
title_fullStr Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling
title_full_unstemmed Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling
title_short Receptor dimerization dynamics as a regulatory valve for plasticity of type I interferon signaling
title_sort receptor dimerization dynamics as a regulatory valve for plasticity of type i interferon signaling
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442803/
https://www.ncbi.nlm.nih.gov/pubmed/26008745
http://dx.doi.org/10.1083/jcb.201412049
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