Alpha interferon (IFN-α) controls homeostasis of hematopoietic stem cells, 
regulates antiviral resistance, inhibits angiogenesis, and suppresses tumor 
growth. This cytokine is often used to treat cancers and chronic viral 
infections. The extent of cellular responses to IFN-α is limited by the 
IFN-induced ubiquitination and degradation of the IFN-α/β receptor chain 1 
(IFNAR1) chain of the cognate receptor. IFNAR1 ubiquitination is facilitated by 
the βTrcp E3 ubiquitin ligase that is recruited to IFNAR1 upon its degron 
phosphorylation, which is induced by the ligand. Here we report identification 
of protein kinase D2 (PKD2) as a kinase that mediates the ligand-inducible 
phosphorylation of IFNAR1 degron and enables binding of βTrcp to the receptor. 
Treatment of cells with IFN-α induces catalytic activity of PKD2 and stimulates 
its interaction with IFNAR1. Expression and kinase activity of PKD2 are required 
for the ligand-inducible stimulation of IFNAR1 ubiquitination and endocytosis 
and for accelerated proteolytic turnover of IFNAR1. Furthermore, inhibition or 
knockdown of PKD2 robustly augments intracellular signaling induced by IFN-α and 
increases the efficacy of its antiviral effects. The mechanisms of the 
ligand-inducible elimination of IFNAR1 are discussed, along with the potential 
medical significance of this regulation.