USP18

The protein encoded by this gene belongs to the ubiquitin-specific proteases (UBP) family of enzymes that cleave ubiquitin from ubiquitinated protein substrates. It is highly expressed in liver and thymus, and is localized to the nucleus. This protein efficiently cleaves only ISG15 (a ubiquitin-like protein) fusions, and deletion of this gene in mice results in a massive increase of ISG15 conjugates in tissues, indicating that this protein is a major ISG15-specific protease. Mice lacking this gene are also hypersensitive to interferon, suggesting a function of this protein in downregulating interferon responses, independent of its isopeptidase activity towards ISG15. [provided by RefSeq, Sep 2011]

Full Name

Ubiquitin Specific Peptidase 18

Function

Involved in the negative regulation of the inflammatory response triggered by type I interferon (PubMed:28165510, PubMed:27325888).
Upon recruitment by STAT2 to the type I IFN receptor subunit IFNAR2 interferes with the assembly of the ternary interferon-IFNAR1-IFNAR2 complex and acts as a negative regulator of the type I IFN signaling pathway (PubMed:28165510).
Also regulates protein ISGylation. Can efficiently cleave only ISG15 fusions including native ISG15 conjugates linked via isopeptide bonds. Necessary to maintain a critical cellular balance of ISG15-conjugated proteins in both healthy and stressed organisms (PubMed:11788588).
Isoform 2
Has enzymatic activity similar to isoform 1 and interferes with type I interferon signaling. Major deISGylation enzyme for nuclear proteins (PubMed:22170061).

Biological Process

Biological Process negative regulation of type I interferon-mediated signaling pathway Source:UniProtKB1 Publication
Biological Process protein deubiquitination Source:GO_Central1 Publication
Biological Process regulation of inflammatory response Source:UniProtKB1 Publication
Biological Process response to bacterium Source:Ensembl
Biological Process response to stilbenoid Source:Ensembl
Biological Process ubiquitin-dependent protein catabolic process Source:InterPro

Cellular Location

Isoform 1
Cytoplasm
Isoform 2
Nucleus
Cytoplasm

Involvement in disease

Pseudo-TORCH syndrome 2 (PTORCH2):
An autosomal recessive multisystem disorder characterized by antenatal onset of intracranial hemorrhage, calcification, brain malformations, liver dysfunction, and often thrombocytopenia. Affected individuals tend to have respiratory insufficiency and seizures, and die in infancy. The phenotype resembles the sequelae of intrauterine infection, but there is no evidence of an infectious agent.