Ubiquitin-specific-processing protease 18 (USP18)

Ubiquitin-specific-processing protease 18 (USP18) is a multifunctional protein that serves as a critical negative regulator of the type I interferon (IFN-I) response and the primary enzyme responsible for deISGylation (UniProt Q9UMW8; [2]). It functions through two distinct mechanisms: its catalytic domain removes the ubiquitin-like modifier ISG15 from target proteins, while its C-terminal domain acts as a non-catalytic scaffold that binds to the IFNAR2 subunit of the IFN-I receptor, blocking the recruitment of Janus kinase 1 (JAK1) [1, 10, 15]. This dual role makes USP18 a vital checkpoint in preventing excessive or chronic IFN-mediated inflammation, but its overexpression in various cancers often promotes tumor survival and resistance to immunotherapy by dampening anti-tumor immune responses [6, 8, 15]. Conversely, loss-of-function mutations in USP18 lead to severe autoinflammatory conditions, such as Pseudo-TORCH syndrome, characterized by systemic interferonopathy and neurological damage [3, 10]. Therapeutic interest in USP18 focuses on developing small molecule inhibitors, such as hyperoside, to sensitize cancer cells to IFN-based therapies and enhance the treatment of chronic viral infections [9, 10].

Other names

Ubiquitin-specific peptidase 18Ubiquitin-specific protease 18UBP43ISG43PTORCH2

USP18 acts as a negative regulator of type I interferon (IFN-I) signaling by binding to the IFNAR2 subunit of the IFN receptor and competing with Janus kinase 1 (JAK1) to prevent signal transduction. It also possesses isopeptidase activity that specifically cleaves the ubiquitin-like modifier ISG15 from its substrate proteins (deISGylation), which can alter protein stability and function. Therapeutic targeting involves small molecule inhibitors that block its catalytic site or disrupt its scaffold interaction with IFNAR2 to enhance IFN sensitivity in cancer and viral infections.