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Glycosylation-Dependent IFN-γR Partitioning in Lipid and Actin Nanodomains Is Critical for JAK Activation.
- Source :
-
Cell [Cell] 2016 Aug 11; Vol. 166 (4), pp. 920-934. Date of Electronic Publication: 2016 Aug 04. - Publication Year :
- 2016
-
Abstract
- Understanding how membrane nanoscale organization controls transmembrane receptors signaling activity remains a challenge. We studied interferon-γ receptor (IFN-γR) signaling in fibroblasts from homozygous patients with a T168N mutation in IFNGR2. By adding a neo-N-glycan on IFN-γR2 subunit, this mutation blocks IFN-γ activity by unknown mechanisms. We show that the lateral diffusion of IFN-γR2 is confined by sphingolipid/cholesterol nanodomains. In contrast, the IFN-γR2 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-γ could not occur. Removing IFN-γR2 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. VIDEO ABSTRACT.<br /> (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Subjects :
- Actins chemistry
Actins metabolism
Animals
COS Cells
Cell Membrane chemistry
Cell Membrane metabolism
Chlorocebus aethiops
Diffusion
Endocytosis
Enzyme Activation
Glycosylation
Humans
Interferon-gamma metabolism
Mycobacterium Infections genetics
Mycobacterium Infections immunology
Receptors, Interferon chemistry
Fibroblasts metabolism
Mutation, Missense
Receptors, Interferon genetics
Receptors, Interferon metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 166
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 27499022
- Full Text :
- https://doi.org/10.1016/j.cell.2016.07.003