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. Function Following its induction by type I interferons (IFN-Is), USP18 carries out three functional interactions: Regulation of IFN-I signaling USP18 inhibits IFN-I signaling by disrupting the receptor complex and the subsequent JAK-STAT signaling pathway. USP18 binds the IFN-receptor 2 subunit (IFNAR2), leading to the displacement of Janus kinase 1. and the dissociation of the cytokine-receptor complex. This process requires STAT2 to traffic USP18 to the receptor These events terminate signaling and draw cells into a refractory state with diminished sensitivity to future stimulation. deISGylation Using the isopeptidase domain, USP18 specifically deconjugates ISG15 (interferon-stimulated gene 15) from tagged proteins. This reaction is termed deISGylation, as the initial conjugation of ISG15 to newly synthesized proteins is termed ISGylation, a process akin to ubiquitination. However, unlike other de-ubiquitinating enzymes, USP18 is specific to ISG15, and exhibits no cross-reactivity with ubiquitin. The consequences of ISGylation and deISGylation are incompletely understood. Stabilization USP18 is stabilized by ISG15, but independently of the ubiquitin-like conjugation. Without ISG15-mediated stabilization, USP18 is degraded at the proteasome. This relationship exists in human, canine and porcine USP18/ISG15, but is absent in murine systems. Promoting factor of HIV infection Macrophages and dendritic cells are usually the first point of contact with pathogens, including lentiviruses. Host restriction factors, including