How USP18 deals with ISG15-modified proteins: structural basis for the specificity of the protease

The ubiquitin-specific protease 18 (USP18) has two major functions: (a) it is a highly specific protease that cleaves the ubiquitin-like modifier ISG15 (interferon-stimulated gene 15) from proteins, and (b) independent from its enzymatic activity USP18 interacts with the type I interferon receptor and shuts off downstream signaling. The structures of USP18 and a USP18-ISG15 complex revealed the molecular basis of the unique specificity of the protease and might shed some light into its interaction with the interferon receptor.