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.