The type I IFN system needs to be regulated not only at the level of its production, but also at the level of responses. We have shown that cells that have responded to IFN-I (primed cells) enter into a long lasting state of refractoriness in particular to IFN α subtypes. Involved in this process is USP18, an IFN-induced protein that binds to the receptor and alters the spatio-temporal dynamics of receptor subunits assembly, attenuating signaling. Thus, USP18 creates a fine-tuning negative feedback loop that not only protects cells from excess signals, but also sets the activity threshold of different IFN subtypes. USP18 is also an isopeptidase that cleaves the ubiquitin-like ISG15 from protein conjugates which accumulate in IFN-stimulated cells. We are interested in better understanding the relationship between the regulatory and catalytic activities of USP18.