Ubiquitin specific peptidase 18 (USP18), also known as UBP43, is a

type I interferon The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T cell, T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p2 ...

receptor repressor and an isopeptidase. In humans, it is encoded by the ''USP18'' gene. USP18 is induced by the immune response to

type I Type 1 or Type I or ''variant'', may refer to: Health *Diabetes mellitus type 1 (also known as "Type 1 Diabetes"), insulin-dependent diabetes * Type I female genital mutilation * Type 1 personality *Type I hypersensitivity (or immediate hypersensit ...

and

III III or iii may refer to: Companies * Information International, Inc., a computer technology company * Innovative Interfaces, Inc., a library-software company * 3i, formerly Investors in Industry, a British investment company Other uses * Ins ...

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 Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...

. Independent of this activity, USP18 is also a member of the deubiquitinating protease family of enzymes. It is known to remove

ISG15 Interferon-stimulated gene 15 (ISG15) is a 17 kDA secreted protein that in humans is encoded by the ''ISG15'' gene. ISG15 is induced by type I interferon (IFN) and serves many functions, acting both as an extracellular cytokine and an intracellul ...

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 Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined **Domain of definition of a partial function **Natural domain of a partial function **Domain of holomorphy of a function * Do ...

. 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 Signal transducer and activator of transcription 2 is a protein that in humans is encoded by the ''STAT2'' gene. It is a member of the STAT protein family. This protein is critical to the biological response of type I interferons (IFNs). STAT2 se ...

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

(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 Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by w ...

. This relationship exists in human,

canine Canine may refer to: Zoology and anatomy * a dog-like Canid animal in the subfamily Caninae ** '' Canis'', a genus including dogs, wolves, coyotes, and jackals ** Dog, the domestic dog * Canine tooth, in mammalian oral anatomy People with the ...

and porcine USP18/ISG15, but is absent in murine systems.

Promoting factor of HIV infection

Macrophage Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

s and

dendritic cell Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. ...

s are usually the first point of contact with pathogens, including

lentivirus ''Lentivirus'' is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lent ...

es. Host restriction factors, including

SAMHD1 SAM domain and HD domain-containing protein 1 is a protein that in humans is encoded by the ''SAMHD1'' gene. SAMHD1 is a cellular enzyme, responsible for blocking replication of HIV in dendritic cells, macrophages, monocytes and resting CD4+ T ly ...

, mediate the innate immune response against these viruses. However, HIV-1 has evolved to circumvent the innate immune response and establishes disseminated infection. It was reported that human USP18 is a novel factor potentially contributing to HIV replication by blocking the antiviral function of p21 in differentiated human myeloid cells. USP18 downregulates

p21 p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated ...

protein expression, which correlates with upregulated intracellular dNTP levels and the antiviral inactive form of SAMHD1. Depletion of USP18 stabilizes p21 protein expression, which correlates with dephosphorylated SAMHD1 and a block to HIV-1 replication.

Clinical significance

USP18-deficiency is a very rare primary immunodeficiency caused by mutations of the USP18 gene. The inheritance is

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

. The clinical disease presents in the perinatal period with life-threatening autoinflammation that mimics TORCH infections, but in the absence of infection. The severe inflammation results from a failure to regulate type I IFN activity, and is therefore considered a type I interferonopathy. This syndrome was initially described to result in death within weeks of birth. Fortunately, this previously lethal condition was recently demonstrated to be curable with a

Janus kinase inhibitor A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JA ...

and intensive supportive care.