Basal ubiquitin-independent internalization of interferon alpha receptor is prevented by Tyk2-mediated masking of a linear endocytic motif.
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 IFNalpha 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.
Kumar
K G Suresh
KG
Department of Animal Biology and Mari Lowe Center for Comparative Oncology Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Varghese
Bentley
B
Banerjee
Anamika
A
Baker
Darren P
DP
Constantinescu
Stefan N
SN
Pellegrini
Sandra
S
Fuchs
Serge Y
SY
D020816:Amino Acid Motifs / Q000502:physiology; D002460:Cell Line; D015536:Down-Regulation / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D053634:TYK2 Kinase / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology*
C507964:IFNAR1 protein, human; D046912:Multiprotein Complexes; D025801:Ubiquitin; D053633:Receptor, Interferon alpha-beta; D053634:TYK2 Kinase; C070139:TYK2 protein, human