Phosphorylation-dependent ubiquitination and ensuing down-regulation and 
lysosomal degradation of the interferon alpha/beta receptor chain 1 (IFNAR1) of 
the receptor for Type I interferons play important roles in limiting the 
cellular responses to these cytokines. These events could be stimulated either 
by the ligands (in a Janus kinase-dependent manner) or by unfolded protein 
response (UPR) inducers including viral infection (in a manner dependent on the 
activity of pancreatic endoplasmic reticulum kinase). Both ligand-dependent and 
-independent pathways converge on phosphorylation of Ser(535) within the IFNAR1 
degron leading to recruitment of beta-Trcp E3 ubiquitin ligase and concomitant 
ubiquitination and degradation. Casein kinase 1 alpha (CK1 alpha) was shown to 
directly phosphorylate Ser(535) within the ligand-independent pathway. Yet given 
the constitutive activity of CK1 alpha, it remained unclear how this pathway is 
stimulated by UPR. Here we report that induction of UPR promotes the 
phosphorylation of a proximal residue, Ser(532), in a pancreatic endoplasmic 
reticulum kinase-dependent manner. This serine serves as a priming site that 
promotes subsequent phosphorylation of IFNAR1 within its degron by CK1 alpha. 
These events play an important role in regulating ubiquitination and degradation 
of IFNAR1 as well as the extent of Type I interferon signaling.