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Diffusion in lipid nanodomains: a key to unlock membrane receptor activation.

The study of the interferon receptors γ (IFN-γR) developed by Christophe Lamaze’s team, Membrane Dynamics and Mechanics of Intracellular Signaling (Institut Curie/CNRS/Inserm), with the cooperation of Hai-Tao He (CIML, Marseille) and Céline Galès (IMMC, Toulouse) teams has come to light in Cell journal.

Receptor spatiotemporal distribution and dynamics at the cell surface is an essential feature of receptor-mediated signal transduction. The nanoscale organization of the plasma membrane (PM) is therefore likely to be a key actor in the control of transmembrane receptors signaling and biological activities. Several patients with Mendelian susceptibility to mycobacterial diseases (MSMD) were shown to present a common mutation resulting in the amino acid substitution T168N which create a new N-glycosylation site in the interferon g receptor subunit IFN-γR2. This inherited modification caused a complete lack of gene response to IFN-γ, a key cytokine for host defense against infection and disease.

Figure 1: IFN-yR receptor complex partitioning at the plasma membrane. At steady state, IFN-yR is dynamically associated with plasma membrane sphingolipid/cholesterol nanodomain. These specific nanodomains are necessary for receptor subunits and associated JAK kinases conformational changes after IFN-y binding. Molecular rearrangements then lead to JAK activation and signal transduction. On the contrary, T168N mutation and excess galectins -1 and -3 (Gal1 & Gal3) binding segregates IFN-yR complex in actin nanodomains and blocks signaling pathway activation. © Elsevier

The precise molecular mechanisms that drive and control the IFN-γR complex conformational changes induced by IFN-γ that lead to JAK activation remain largely elusive. To address these questions, we combined fluorescence correlation spectroscopy, bioluminescence resonance energy transfer, and immunochemical experiments to investigate the molecular dynamics, conformational changes and signaling of the activated IFN-γR in cells from control and homozygous patients with the IFN-γR2 T168N congenital disorder. Our experimental data revealed that the control by galectins of the dynamic partition of the IFN-γR between lipid nanodomains and the actin cytoskeleton is critical for JAK/STAT signaling. Excess and/or abnormal binding of galectins -1 & -3 to the mutated IFN-γR2 T168N confines IFN-γR lateral diffusion in actin nanodomains that, in contrast to lipid nanodomains, does not allow the IFN-γR conformational changes required for JAK/STAT signaling. Galectin depletion restored lateral diffusion in lipid nanodomains and JAK/STAT signaling in patient cells whereas galectin addition impaired these two processes in control cells expressing the wild type IFN-γR2. These results establish therefore the physiological relevance of lipid nanodomains in receptor dynamics and transmembrane signaling activity at the PM and the unsuspected key role of receptor glycosylation in this process.

Link for Cell video abstract:

 

Original article
Glycosylation-Dependent IFN-
gR Partitioning in Lipid and Actin Nanodomains is Critical for JAK Activation
Cell / August 2016
Cédric M. Blouin, Yannick Hamon, Pauline Gonnord, Cédric Boularan, Jérémy Kagan, Christine Viaris de Lesegno, Richard Ruez, Sébastien Mailfert, Nicolas Bertaux, Damarys Loew, Christian Wunder, Ludger Johannes, Guillaume Vogt, Francesc-Xabier Contreras, Didier Marguet, Jean-Laurent Casanova, Céline Galés, Hai-Tao He and Christophe Lamaze.

 

Cedric BLOUIN, PhD