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Vol. 17, Issue 7, 2896-2909, July 2006

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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

Marta Marchetti^*,, Marie-Noelle Monier^*,, Alexandre Fradagrada^*, Keith Mitchell^*, Florence Baychelier, Pierre Eid, Ludger Johannes^*, and Christophe Lamaze^*

*Laboratoire Trafic et Signalisation, UMR144 Curie/CNRS, Institut Curie, 75248 Paris Cedex 05, France; and Laboratoire d’Oncologie Virale, CNRS-UPR 9045, 94801 Villejuif, France

Submitted January 26, 2006; Revised April 3, 2006; Accepted April 11, 2006
Monitoring Editor: Sandra Schmid

Type I (/) and type II () 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- and IFN- receptors are internalized by a classical clathrin- and dynamin-dependent endocytic pathway. Although inhibition of clathrin-dependent endocytosis blocked the uptake of IFN- and IFN- receptors, this inhibition only affected IFN-–induced Stat1 and Stat2 signaling. Furthermore, the antiviral and antiproliferative activities induced by IFN- but not IFN- were also affected. Finally, we show that, unlike IFN- receptors, activated IFN- 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.

These authors contributed equally to this work.

Address correspondence to: Christophe Lamaze ( christophe.lamaze{at}curie.fr)

Abbreviations used: DRM, detergent resistant membrane; IFN-R, interferon receptor; IFNAR, interferon alpha receptor; IFNGR, interferon gamma receptor; RNAi, RNA interference; Stat, signal transducer and activator of transcription; Tf, transferrin.

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