Receptor Dimerization Dynamics As a Regulatory Valve for Plasticity of Type I Interferon Signaling

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2015 May 27

PMID 26008745

Citations 72

Authors

Stephan Wilmes

Oliver Beutel

Zhi Li

Veronique Francois-Newton

Christian P Richter

Dennis Janning

Cindy Kroll

Patrizia Hanhart

Katharina Hotte

Changjiang You

Gilles Uze

Sandra Pellegrini

Jacob Piehler

Affiliations

Soon will be listed here.

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.

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