TYK2 activity promotes the ligand-induced IFNAR1 proteolysis

International audienceThe type I interferon receptor is a heterodimer of two transmembrane chains, IFNAR1 and IFNAR2, which are associated to the tyrosine kinases Tyk2 and Jak1 respectively. Ligand-induced down-regulation of the type I interferon receptor represents a major mechanism of negative regulation of signaling and involves internalization and lysosomal degradation of IFNAR1. Interferon {alpha} promotes phosphorylation of IFNAR1 on serine 535, followed by recruitment of the {beta}-TrCP2 E3 ubiquitin ligase, 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 Tyk2 function in steps that precede and succeed serine phosphorylation and ubiquitination of IFNAR1 in response to the ligand. Here we show that catalytic activation of Tyk2 is not essential for IFNAR1 internalization, but is required for the ligand-induced IFNAR1 serine phosphorylation, ubiquitination and efficient lysosomal proteolysis