Ubiquitin specific peptidase 18 (USP18)

Ubiquitin specific peptidase 18 (USP18) is an enzyme in humans encoded by the USP18 gene. It belongs to the ubiquitin-specific protease family and specifically cleaves the ubiquitin-like modifier ISG15 from substrate proteins—a process called deISGylation. In addition to its isopeptidase activity, USP18 serves as a key negative regulator of type I interferon receptor signaling by binding IFNAR2 and disrupting JAK-STAT pathway activation. USP18 functions as a post-translational modifier and a critical immune checkpoint, controlling inflammation, antiviral responses, and cell fate. Its deregulation contributes to diverse pathologies including autoinflammatory syndromes, several cancers, infectious diseases, and metabolic disorders. Loss-of-function mutations cause severe interferonopathies, while gain-of-function or increased expression facilitate viral infection and tumor survival.

Other names

UBP43ISG15 isopeptidase

Drugs targeting USP18 would likely act by inhibiting its isopeptidase activity (preventing deISGylation), modulating its ability to negatively regulate interferon signaling (e.g. disruption of IFNAR2 binding), or affecting its stability/expression in disease contexts.