USP18 (UBiquitin Specific Peptidase 18) - A Key Regulator of ISG15 and Interferon Signaling
Explore the USP18 gene: its genomic context, protein function, role in interferon signaling and ISG15 deconjugation, associated diseases, tissue expression, and mutation landscape.
Gene Information Card
| Symbol | USP18 |
|---|---|
| Full Name | Ubiquitin Specific Peptidase 18 |
| Gene Type | Protein coding |
| Chromosomal Location | 22q11.21 |
| NCBI Gene ID | 11274 ncbi.nlm.nih.gov/gene/11274 |
| Ensembl ID | ENSG00000186591 |
| UniProt ID | Q9UMW8 |
| OMIM ID | 607057 |
| HGNC ID | 12615 |
| Aliases | UBP43, ISG43, PTORCH2 |
Description
USP18 (Ubiquitin Specific Peptidase 18), also known as UBP43, is a cysteine protease that specifically removes the ubiquitin-like modifier ISG15 from target proteins. It is a critical negative regulator of type I interferon (IFN) signaling, functioning by binding to the IFN-alpha/beta receptor subunit 2 (IFNAR2) and inhibiting downstream JAK-STAT signaling. USP18 is essential for the termination of IFN responses and plays a key role in immune regulation, antiviral defense, and cellular homeostasis. Its expression is highly inducible by type I interferons, forming a negative feedback loop.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Pseudo-TORCH Syndrome 2 | Biallelic loss-of-function mutations in USP18 lead to unregulated type I interferon signaling, causing severe autoinflammation and brain developmental defects. | OMIM, PubMed (Meuwissen et al., 2016) |
| Susceptibility to Viral Infections | Altered USP18 expression or function can impair the regulation of interferon responses, potentially leading to enhanced or prolonged inflammation during viral infections. | PubMed (Basters et al., 2018) |
| Cancer (Various) | USP18 expression is dysregulated in several cancers. Its role is context-dependent, either promoting or suppressing tumor growth by modulating ISG15 conjugation and interferon signaling pathways. | PubMed (Mustachio et al., 2018) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | 9.2 | Medium |
| Spleen | 7.8 | Medium |
| Lung | 6.5 | Low |
| Kidney | 5.1 | Low |
| Brain | 2.3 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| Hep G2 (Liver) | 12.5 | High expression |
| A-549 (Lung) | 8.1 | Medium expression |
| K-562 (Bone Marrow) | 4.3 | Low expression |
| MCF7 (Breast) | 2.9 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.404T>C (p.Leu135Pro) | Missense | Rare | Loss-of-function; associated with Pseudo-TORCH Syndrome 2. |
| c.733C>T (p.Arg245Ter) | Nonsense | Rare | Loss-of-function; leads to truncated protein and Pseudo-TORCH Syndrome 2. |
| c.1A>G (p.Met1?) | Start Codon Loss | Rare | Loss-of-function; prevents translation initiation. |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations in USP18, typically biallelic, result in a complete or near-complete loss of ISG15 protease activity and the inability to negatively regulate type I interferon signaling. This leads to uncontrolled IFN signaling, causing severe autoinflammatory conditions like Pseudo-TORCH Syndrome 2.
Gain of Function (GOF)
Gain-of-function mutations in USP18 are not well-documented in the literature. Overexpression of wild-type USP18, however, can act as a gain-of-function in a cellular context, leading to enhanced deISGylation and potentially contributing to tumorigenesis or immune evasion in certain cancers.
Dominant Negative (DN)
Dominant-negative effects are not a typical mechanism for USP18 mutations. The protein functions as a monomer, and disease-causing mutations are generally recessive, requiring both alleles to be affected for a phenotype to manifest.
View complete mutation data：
Gene Ontology (GO)
| • cysteine-type peptidase activity | • ISG15-specific protease activity |
| • protein binding | • type I interferon receptor binding |
| • negative regulation of type I interferon-mediated signaling pathway | • ISG15-protein conjugation |
| • innate immune response | • response to virus |
| • protein deubiquitination |
Pathways
• ISG15 antiviral mechanism
• Interferon alpha/beta signaling
• Cytokine Signaling in Immune system
• Immune System
Protein Summary
The USP18 protein is a 43 kDa cysteine protease belonging to the ubiquitin-specific protease (USP) family. It is characterized by its high specificity for cleaving ISG15, a ubiquitin-like modifier, from target proteins. Structurally, it contains a catalytic triad (Cys64, His334, Asp351) essential for its protease activity. Beyond its enzymatic function, USP18 acts as a key negative regulator of type I interferon signaling by binding to the intracellular domain of IFNAR2, thereby preventing the association and activation of JAK1 and subsequent STAT1 phosphorylation. This non-catalytic function is crucial for maintaining immune homeostasis and preventing excessive inflammation. USP18 expression is strongly induced by type I interferons, creating a negative feedback loop that tightly controls the amplitude and duration of interferon responses.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| USP18 Knockout HEK293 Cell Line | EDJ-KQ2453 | Human | 11274 | Details Get a Quote |
| USP18 Knockout A-549 Cell Line | EDJ-KQ22984 | Human | 11274 | Details Get a Quote |
| USP18 Knockout HCT 116 Cell Line | EDJ-KQ22985 | Human | 11274 | Details Get a Quote |
| USP18 Knockout HeLa Cell Line | EDJ-KQ22986 | Human | 11274 | Details Get a Quote |
