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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 IFN?2 is potently down-regulated after the first wave of gene induction, while IFN?, 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 IFN? is maintained over longer times compared with IFN?2 as a temporally encoded cause of functional receptor plasticity.

SUBMITTER: Wilmes S

PROVIDER: S-EPMC4442803 | biostudies-other | 2015 May

REPOSITORIES: biostudies-other

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

Wilmes Stephan S Beutel Oliver O Li Zhi Z Francois-Newton Véronique V Richter Christian P CP Janning Dennis D Kroll Cindy C Hanhart Patrizia P Hötte Katharina K You Changjiang C Uzé Gilles G Pellegrini Sandra S Piehler Jacob J

The Journal of cell biology 20150501 4

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 ...[more]

PMID: 26008745

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

Publications

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

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