Enzymatic and non-enzymatic functions of USP18

Figure 1. Type I interferons (IFN) bind to a dimeric receptor (IFNAR1 and IFNAR2) on the cell surface to activate the intracellular kinases TYK2 and JAK1. These kinases recruit and phosphorylate the transcription factors STAT1 and STAT2 which subsequently bind the transcription factor IRF9 and translocate into the nucleus. The trimeric complex binds to the ISRE element in promoters of interferon-stimulated genes (ISGs) and induces the expression of ISGs including USP18, ISG15 and the E1, E2 and E3 enzymes that catalyse ISGylation of substrate proteins. USP18 deISGylates target proteins by cleaving the isopeptide bond between the C-terminus of ISG15 and a lysine residue of the substrate protein. USP18 also interacts with IFNAR2 and STAT2 to block type I interferon signalling in a protease-independent manner. Abbreviations: IRF9, IFN-regulatory factor 9, JAK1, Janus activated kinase 1; STAT, signal transducer and activator of transcription; TYK2, tyrosine kinase 1.