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

• Published in: The Journal of biological chemistry 2008-07, Vol.283 (27), p.18566-18572
• Main Authors: Kumar, K.G. Suresh, Varghese, Bentley, Banerjee, Anamika, Baker, Darren P., Constantinescu, Stefan N., Pellegrini, Sandra, Fuchs, Serge Y.
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Amino Acid Motifs - physiology; Cell Line; Down-Regulation; Down-Regulation - physiology; Endocytosis; Endocytosis - physiology; Humans; Immunology; Life Sciences; Multiprotein Complexes; Multiprotein Complexes - genetics; Multiprotein Complexes - metabolism; Protein Synthesis, Post-Translational Modification, and Degradation; Receptor, Interferon alpha-beta; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - metabolism; Signal Transduction; Signal Transduction - physiology; TYK2 Kinase; TYK2 Kinase - genetics; TYK2 Kinase - metabolism; Ubiquitin; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitination; Ubiquitination - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M800991200

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 IFNα 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.