title: The tyrosine kinase Tyk2 controls IFNAR1 cell surface expression.
abstract: The four mammalian Jak tyrosine kinases are non-covalently associated with cell surface receptors binding helical bundled cytokines. In the type I interferon receptor, Tyk2 associates with the IFNAR1 receptor subunit and positively influences ligand binding to the receptor complex. Here, we report that Tyk2 is essential for stable cell surface expression of IFNAR1. In the absence of Tyk2, mature IFNAR1 is weakly expressed on the cell surface. Rather, it is localized into a perinuclear endosomal compartment which overlaps with that of recycling transferrin receptors and with early endosomal antigen-1 (EEA1) positive vesicles. Conversely, co-expressed Tyk2 greatly enhances surface IFNAR1 expression. Importantly, we demonstrate that Tyk2 slows down IFNAR1 degradation and that this is due, at least in part, to inhibition of IFNAR1 endocytosis. In addition, Tyk2 induces plasma membrane relocalization of the R2 subunit of the interleukin-10 receptor. These results reveal a novel function of a Jak protein on internalization of a correctly processed cytokine receptor. This function is distinct from the previously reported effect of other Jak proteins on receptor exit from the endoplasmic reticulum.
authors.affiliation: Unité de Signalisation des Cytokines, CNRS URA 1961, Unité de Biologie des Interactions Cellulaires, CNRS URA 1960, Institut Pasteur, Paris 75724 cedex 15, France.
authors.forename: Josiane
authors.initials: J
authors.lastname: Ragimbeau
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dondi
authors.forename: Andrés
authors.initials: A
authors.lastname: Alcover
authors.forename: Pierre
authors.initials: P
authors.lastname: Eid
authors.forename: Gilles
authors.initials: G
authors.lastname: Uzé
authors.forename: Sandra
authors.initials: S
authors.lastname: Pellegrini
mesh_terms: D002460:Cell Line; D004705:Endocytosis / Q000502:physiology; D011992:Endosomes / Q000378:metabolism; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism; D053701:Receptors, Interleukin-10; D053634:TYK2 Kinase; D014162:Transfection; D014168:Transferrin / Q000378:metabolism; D033921:Vesicular Transport Proteins
chemical_list: D005456:Fluorescent Dyes; C507964:IFNAR1 protein, human; D008565:Membrane Proteins; D011506:Proteins; D017471:Receptors, Interferon; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D014168:Transferrin; D033921:Vesicular Transport Proteins; C093846:early endosome antigen 1; D053633:Receptor, Interferon alpha-beta; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human