TYK2 activity promotes ligand-induced IFNAR1 proteolysis.
The type I IFNR (interferon receptor) is a heterodimer composed of two transmembrane chains, IFNAR1 (interferon-alpha receptor 1 subunit) and IFNAR2, which are associated with the tyrosine kinases Tyk2 and Jak1 (Janus kinase 1) respectively. Ligand-induced down-regulation of the type I IFNR is a major mechanism of negative regulation of cellular signalling and involves the internalization and lysosomal degradation of IFNAR1. IFNalpha promotes the phosphorylation of IFNAR1 on Ser535, followed by recruitment of the E3 ubiquitin ligase, beta-TrCP2 (beta-transducin repeats-containing protein 2), ubiquitination of IFNAR1 and proteolysis. The non-catalytic role of Tyk2 in sustaining the steady-state IFNAR1 level at the plasma membrane is well documented; however, little is known about the function of Tyk2 in the steps that precede and succeed serine phosphorylation and ubiquitination of IFNAR1 in response to ligand binding. In the present study, we show that catalytic activation of Tyk2 is not essential for IFNAR1 internalization, but is required for ligand-induced IFNAR1 serine phosphorylation, ubiquitination and efficient lysosomal proteolysis.
Marijanovic
Zrinka
Z
Cytokine Signalling Unit, CNRS URA 1961, Pasteur Institute, Paris 75724, France.
Ragimbeau
Josiane
J
Kumar
K G Suresh
KG
Fuchs
Serge Y
SY
Pellegrini
Sandra
S
D019921:Biotinylation; D002384:Catalysis; D002678:Chimera; D005354:Fibrosarcoma / Q000235:genetics; D006207:Half-Life; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology; D007457:Iodine Radioisotopes; D007668:Kidney / Q000166:cytology; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta; D017467:Receptors, Erythropoietin / Q000502:physiology; D017471:Receptors, Interferon / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D053634:TYK2 Kinase; D014162:Transfection; D014407:Tumor Cells, Cultured
C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; D016898:Interferon-alpha; D007457:Iodine Radioisotopes; D008024:Ligands; D008565:Membrane Proteins; D017467:Receptors, Erythropoietin; D017471:Receptors, Interferon; D053633:Receptor, Interferon alpha-beta; D012694:Serine; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human