Journal
CELL
Volume 166, Issue 4, Pages 920-934Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.07.003
Keywords
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Funding
- Institut Curie
- INSERM
- CNRS
- Agence Nationale de la Recherche (ANR) [NANOSTAT-15-CE11-0025-01, ANR-10-BLAN-1509, ANR-11-LABX-0054, ANR-10-BLAN-1214, ANR-10-INBS-04-01, ANR-11-IDEX-0001-02]
- Institut National du Cancer (INCa) [PLBIO12-203]
- Marie Curie Actions-Networks for Initial Training
- Spanish Ministry of Economy [BFU2012-33103]
- Ligue Nationale contre le Cancer
- program Investissements d'Avenir''
- Agence Nationale de la Recherche (ANR) [ANR-10-BLAN-1214, ANR-10-BLAN-1509] Funding Source: Agence Nationale de la Recherche (ANR)
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Understanding how membrane nanoscale organization controls transmembrane receptors signaling activity remains a challenge. We studied interferon-gamma receptor (IFN-gamma R) signaling in fibroblasts from homozygous patients with a T168N mutation in IFNGR2. By adding a neo-N-glycan on IFN-gamma R2 subunit, this mutation blocks IFN-gamma activity by unknown mechanisms. We show that the lateral diffusion of IFN-gamma R2 is confined by sphingolipid/cholesterol nanodomains. In contrast, the IFN-gamma R2 T168N mutant diffusion is confined by distinct actin nanodomains where conformational changes required for Janus-activated tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) activation by IFN-gamma could not occur. Removing IFN-gamma R2 T168N-bound galectins restored lateral diffusion in lipid nanodomains and JAK/STAT signaling in patient cells, whereas adding galectins impaired these processes in control cells. These experiments prove the critical role of dynamic receptor interactions with actin and lipid nanodomains and reveal a new function for receptor glycosylation and galectins. Our study establishes the physiological relevance of membrane nanodomains in the control of transmembrane receptor signaling in vivo.
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