title: Stat-mediated signaling induced by type I and type II interferons (IFNs) is differentially controlled through lipid microdomain association and clathrin-dependent endocytosis of IFN receptors.
abstract: Type I (alpha/beta) and type II (gamma) interferons (IFNs) bind to distinct receptors, although they activate the same signal transducer and activator of transcription, Stat1, raising the question of how signal specificity is maintained. Here, we have characterized the sorting of IFN receptors (IFN-Rs) at the plasma membrane and the role it plays in IFN-dependent signaling and biological activities. We show that both IFN-alpha and IFN-gamma receptors are internalized by a classical clathrin- and dynamin-dependent endocytic pathway. Although inhibition of clathrin-dependent endocytosis blocked the uptake of IFN-alpha and IFN-gamma receptors, this inhibition only affected IFN-alpha-induced Stat1 and Stat2 signaling. Furthermore, the antiviral and antiproliferative activities induced by IFN-alpha but not IFN-gamma were also affected. Finally, we show that, unlike IFN-alpha receptors, activated IFN-gamma receptors rapidly become enriched in plasma membrane lipid microdomains. We conclude that IFN-R compartmentalization at the plasma membrane, through clathrin-dependent endocytosis and lipid-based microdomains, plays a critical role in the signaling and biological responses induced by IFNs and contributes to establishing specificity within the Jak/Stat signaling pathway.
authors.affiliation: Laboratoire Trafic et Signalisation, UMR144 Curie/CNRS, Institut Curie, 75248 Paris Cedex 05, France.
authors.forename: Marta
authors.initials: M
authors.lastname: Marchetti
authors.forename: Marie-Noelle
authors.initials: MN
authors.lastname: Monier
authors.forename: Alexandre
authors.initials: A
authors.lastname: Fradagrada
authors.forename: Keith
authors.initials: K
authors.lastname: Mitchell
authors.forename: Florence
authors.initials: F
authors.lastname: Baychelier
authors.forename: Pierre
authors.initials: P
authors.lastname: Eid
authors.forename: Ludger
authors.initials: L
authors.lastname: Johannes
authors.forename: Christophe
authors.initials: C
authors.lastname: Lamaze
mesh_terms: D021581:Active Transport, Cell Nucleus; D002462:Cell Membrane / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism* / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D021962:Membrane Microdomains / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D021381:Protein Transport; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D002966:Clathrin; C086185:IFNGR2 protein, human; D016898:Interferon-alpha; D008565:Membrane Proteins; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma