title: Glycosylation-Dependent IFN-γR Partitioning in Lipid and Actin Nanodomains Is Critical for JAK Activation.
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.
authors: Institut Curie, PSL Research University, CNRS UMR3666, INSERM U1143, 75005 Paris, France.
authors: Cédric M
authors: CM
authors: Blouin
authors: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France.
authors: Yannick
authors: Y
authors: Hamon
authors: Centre de Physiologie Toulouse-Purpan (CPTP), INSERM U1043, 31300 Toulouse, France.
authors: Pauline
authors: P
authors: Gonnord
authors: Institut des Maladies Métaboliques et Cardiovasculaires, Université Toulouse III Paul Sabatier, INSERM U1048, 31432 Toulouse, France.
authors: Cédric
authors: C
authors: Boularan
authors: Institut Curie, PSL Research University, CNRS UMR3666, INSERM U1143, 75005 Paris, France.
authors: Jérémy
authors: J
authors: Kagan
authors: Institut Curie, PSL Research University, CNRS UMR3666, INSERM U1143, 75005 Paris, France.
authors: Christine
authors: C
authors: Viaris de Lesegno
authors: Institut Curie, PSL Research University, CNRS UMR3666, INSERM U1143, 75005 Paris, France.
authors: Richard
authors: R
authors: Ruez
authors: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France.
authors: Sébastien
authors: S
authors: Mailfert
authors: Institut Fresnel, Aix Marseille Université, Centrale Marseille, CNRS, Marseille, France.
authors: Nicolas
authors: N
authors: Bertaux
authors: Proteomics and Mass Spectrometry Laboratory, Institut Curie, PSL Research University, 75005 Paris, France.
authors: Damarys
authors: D
authors: Loew
authors: Institut Curie, PSL Research University, CNRS UMR3666, INSERM U1143, 75005 Paris, France.
authors: Christian
authors: C
authors: Wunder
authors: Institut Curie, PSL Research University, CNRS UMR3666, INSERM U1143, 75005 Paris, France.
authors: Ludger
authors: L
authors: Johannes
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Hospital for Sick Children, Imagine Institute, INSERM UMR1163, 75015 Paris, France; University Paris Descartes, 75006 Paris, France.
authors: Guillaume
authors: G
authors: Vogt
authors: Instituto Biofísica (UPV/EHU, CSIC), P.O. Box 644, 48080 Bilbao, Spain; Departamento de Bioquímica y Biologia Molecular, Universidad del País Vasco, P.O. Box 644, 48080 Bilbao, Spain; IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain.
authors: Francesc-Xabier
authors: FX
authors: Contreras
authors: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France.
authors: Didier
authors: D
authors: Marguet
authors: St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Necker Hospital for Sick Children, Imagine Institute, INSERM UMR1163, 75015 Paris, France; University Paris Descartes, 75006 Paris, France; Howard Hughes Medical Institute, New York, NY 10065, USA; Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, 75015 Paris, France.
authors: Jean-Laurent
authors: JL
authors: Casanova
authors: Institut des Maladies Métaboliques et Cardiovasculaires, Université Toulouse III Paul Sabatier, INSERM U1048, 31432 Toulouse, France.
authors: Céline
authors: C
authors: Galès
authors: Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France. Electronic address: he@ciml.univ-mrs.fr.
authors: Hai-Tao
authors: HT
authors: He
authors: Institut Curie, PSL Research University, CNRS UMR3666, INSERM U1143, 75005 Paris, France. Electronic address: christophe.lamaze@curie.fr.
authors: Christophe
authors: C
authors: Lamaze
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002522:Chlorocebus aethiops; D004058:Diffusion; D004705:Endocytosis; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020125:Mutation, Missense; D009164:Mycobacterium Infections / Q000235:genetics / Q000276:immunology; D017471:Receptors, Interferon / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000199:Actins; C086185:IFNGR2 protein, human; D017471:Receptors, Interferon; D007371:Interferon-gamma