THE AMINO-TERMINAL REGION OF TYK2 SUSTAINS THE LEVEL OF INTERFERON-ALPHA RECEPTOR-1, A COMPONENT OF THE INTERFERON-ALPHA BETA RECEPTOR/

Tyk2 belongs to the Janus kinase (JAK) family of receptor associated t yrosine kinases, characterized by a large N-terminal region, a kinase- like domain and a tyrosine kinase domain, It was previously shown that Tyk2 contributes to interferon-alpha (IFN-alpha) signaling not only c atalytically, but also as an essential intracellular component of the receptor complex, being required for high affinity binding of IFN-alph a. For this function the tyrosine kinase domain was found to be dispen sable. Here, it is shown that mutant cells lacking Tyk2 have significa ntly reduced IFN-alpha receptor 1 (IFNAR1) protein level, whereas the mRNA level is unaltered, Expression of the N-terminal region of Tyk2 i n these cells reconstituted wild-type IFNAR1 level, but did not restor e the binding activity of the receptor, Studies of mutant Tyk2 forms d eleted at the N terminus indicated that the integrity of the N-termina l region is required to sustain IFNAR1, These studies also showed that the N-terminal region does not directly modulate the basal autophosph orylation activity of Tyk2, but it is required for efficient in vitro IFNAR1 phosphorylation and for rendering the enzyme activatable by IFN -alpha. Overall, these results indicate that distinct Tyk2 domains pro vide different functions to the receptor complex: the N-terminal regio n sustains IFNAR1 level, whereas the kinase-like domain provides a fun ction toward high affinity ligand binding.