USP18
Description
The USP18 (ubiquitin specific peptidase 18) is a protein-coding gene located on chromosome 22.
Ubiquitin specific peptidase 18 (USP18), also known as UBP43, is a type I interferon receptor repressor and an isopeptidase. In humans, it is encoded by the USP18 gene. USP18 is induced by the immune response to type I and III interferons, and serves as a negative regulator of type I interferon, but not type III interferon. Loss of USP18 results in increased responsiveness to type I interferons and life-threatening autoinflammatory disease in humans due to the negative regulatory function of USP18 in interferon signal transduction. Independent of this activity, USP18 is also a member of the deubiquitinating protease family of enzymes. It is known to remove ISG15 conjugates from a broad range of protein substrates, a process known as deISGylation.
== Structure == The USP18 gene consists of 11 exons that encode a 43 kDa protein. The USP18 protein adopts the characteristic hand-like structure of ubiquitin-specific-proteases (USPs), which consists of a finger, palm and thumb domain. At the interface of the palm and thumb domain lies the catalytic site composed of the cysteine protease triad (cysteine, a histidine and an aspartate or asparagine). The C-terminus of USP18 is primarily responsible for negative regulation of interferon-I signaling.
USP18 is an interferon-induced ISG15-specific protease that plays a crucial role in maintaining the balance of ISG15-conjugated proteins in cells. It regulates protein ISGylation by efficiently cleaving ISG15 conjugates linked via isopeptide bonds. USP18 also regulates T-cell activation and T-helper 17 (Th17) cell differentiation by deubiquitinating TAK1, which is likely to keep TAK1-TAB complexes in steady conditions. This action restricts activation of NF-kappa-B, NFAT, and JNK as well as expression of IL2 in T-cells after TCR activation. USP18 acts as a molecular adapter with USP20 to promote innate antiviral response through deubiquitinating STING1. It is involved in the negative regulation of the inflammatory response triggered by type I interferon. Upon recruitment by STAT2 to the type I interferon receptor subunit IFNAR2, USP18 interferes with the assembly of the ternary interferon-IFNAR1-IFNAR2 complex and acts as a negative regulator of the type I interferon signaling pathway.
USP18 is also known as ISG43, PTORCH2, UBP43.
