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J. Biol. Chem., Vol. 283, Issue 27, 18566-18572, July 4, 2008

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Basal Ubiquitin-independent Internalization of Interferon Receptor Is Prevented by Tyk2-mediated Masking of a Linear Endocytic Motif^*

K. G. Suresh Kumar¹, Bentley Varghese, Anamika Banerjee, Darren P. Baker, Stefan N. Constantinescu^¶2, Sandra Pellegrini^||, and Serge Y. Fuchs³

From the Department of Animal Biology and Mari Lowe Center for Comparative Oncology Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104, Biogen Idec Inc., Cambridge, Massachusetts 02142, the ^¶Ludwig Institute for Cancer Research and Université Catholique de Louvain, Christian de Duve Institute of Cellular Pathology, Brussels B-1200, Belgium, and the ^||Unité de Signalisation des Cytokines, CNRS URA 1961, Institut Pasteur, Paris 75724, France

Linear endocytic motifs of signaling receptors as well as their ubiquitination determine the rate of ligand-induced endocytosis that mediates down-regulation of these receptors and restricts the magnitude and duration of their respective signal transduction pathways. We previously hypothesized that, in the absence of its cognate ligand, type I interferon (IFN), the IFN receptor chain 1 (IFNAR1) receptor chain is protected from basal endocytosis by a hypothetical masking complex that prevents the Tyr-based endocytic motif within IFNAR1 from interacting with components of the adaptin protein complex 2 (AP2). Here we identify a member of the Janus kinase (Jak) family, Tyk2, as a component of such a masking complex. In the absence of ligand or of receptor chain ubiquitination, binding of Janus kinase Tyk2 within the proximity of the Tyr-based linear motif of IFNAR1 is required to prevent IFNAR1 internalization and to maintain its cell surface expression. Furthermore, interaction experiments revealed that Tyk2 physically shields this Tyr-based motif from the recognition by the AP50 subunit of AP2. These data delineate a long-sought ligand- and ubiquitin-independent mechanism by which Tyk2 contributes to both the regulation of total IFNAR1 levels as well as the regulation of the cell surface density of this receptor chain.

Received for publication, February 6, 2008 , and in revised form, May 6, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant CA92900 from the NCI, Public Health Service. This work was also supported by grants from The Mari Lowe Center for Comparative Oncology Research (to S. Y. F.), grants from the Fédération Belge Contre le Cancer, the Fonds National de la Recherche Scientifique (FNRS)-Belgium (Mandat d'impulsion), the Maggy and Robert de Hovre Foundation, the Fonds Speciaux de Recherche of the Université Catholique de Louvain (to S. N. C.), and by the grant 3158 of the Association pour la Recherche sur le Cancer (to S. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Progenra Inc, 271A Great Valley Parkway, Malvern, PA 19355.

² A Research Associate of FNRS, Belgium.

³ To whom correspondence should be addressed: Dept. of Animal Biology, University of Pennsylvania, 380 S. University Ave., Hill 316, Philadelphia, PA 19104-4539. Tel.: 215-573-6949; Fax: 215-746-2295; E-mail: syfuchs{at}vet.upenn.edu.

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