ISG15 Gene - Function, Disease Associations, and Clinical Significance
Comprehensive guide to ISG15 (Ubiquitin-like modifier ISG15): genomic data, expression, mutations, and pathways.
Gene Information Card
| Symbol | ISG15 |
|---|---|
| Full Name | ISG15 ubiquitin-like modifier |
| Gene Type | protein coding |
| Chromosomal Location | 1p36.33 |
| NCBI Gene ID | 9636 ncbi.nlm.nih.gov/gene/9636 |
| Ensembl ID | ENSG00000187608 |
| UniProt ID | P05161 |
| OMIM ID | 147571 |
| HGNC ID | 4053 |
| Aliases | G1P2, IFI15, UCRP, IP17 |
Description
ISG15 (ISG15 ubiquitin-like modifier) encodes a ubiquitin-like protein that is strongly induced by type I interferons. ISG15 is conjugated to target proteins (ISGylation) and also exists as a free secreted molecule with cytokine-like functions. It plays critical roles in antiviral defense, immune regulation, and protein homeostasis. Mutations in ISG15 cause susceptibility to mycobacterial disease and are associated with neurological abnormalities.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Immunodeficiency 38 (IMD38) | Loss-of-function mutations in ISG15 lead to impaired ISGylation and increased interferon signaling, causing susceptibility to mycobacterial disease. | OMIM: 616126; ClinVar: pathogenic variants |
| Aicardi-Goutières syndrome (AGS) - atypical | ISG15 deficiency results in enhanced type I interferon production due to reduced USP18 stability, leading to interferonopathy. | OMIM: 147571; PMID: 25533962 |
| Systemic lupus erythematosus (SLE) - susceptibility | ISG15 overexpression and ISGylation contribute to interferon signature and autoimmunity. | GWAS and expression studies; PMID: 25605271 |
| Cancer (various) | ISG15 is overexpressed in several cancers and promotes tumor cell proliferation, invasion, and immune evasion via ISGylation and secreted forms. | COSMIC: overexpression; PMID: 29622471 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Blood | 12.3 | Medium |
| Spleen | 8.5 | Low |
| Lung | 6.2 | Low |
| Liver | 4.1 | Low |
| Brain | 2.0 | Not detected |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 15.2 | High baseline; induced by IFN |
| A549 | 10.8 | Induced by IFN-beta |
| HUVEC | 8.3 | Induced by IFN-alpha |
| K562 | 5.1 | Low baseline |
| MCF7 | 7.4 | Moderate; induced by IFN |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.336C>A (p.Cys112Ter) | Nonsense | Rare | Loss of function; causes IMD38 |
| c.337G>T (p.Glu113Ter) | Nonsense | Rare | Loss of function; causes IMD38 |
| c.146T>C (p.Leu49Pro) | Missense | Rare | Loss of function; impaired ISGylation |
| c.338G>A (p.Trp113Ter) | Nonsense | Rare | Loss of function; causes IMD38 |
Mutation functional classification
Loss of Function (LOF)
Most pathogenic ISG15 mutations are loss-of-function, leading to absent or non-functional protein, resulting in impaired ISGylation and increased interferon signaling.
Gain of Function (GOF)
No gain-of-function mutations have been reported in ISG15.
Dominant Negative (DN)
No dominant-negative mutations have been documented.
View complete mutation data：
Gene Ontology (GO)
| • protein conjugation | • ISG15-protein conjugation |
| • cytokine activity | • interferon-gamma-mediated signaling pathway |
| • type I interferon signaling pathway | • antiviral defense |
| • protein modification process | • immune response |
Pathways
• ISG15 conjugation pathway
• Type I interferon signaling
• Antiviral defense
• Protein ubiquitination (ISGylation)
Protein Summary
ISG15 is a 17 kDa ubiquitin-like protein that is covalently conjugated to target proteins via a three-enzyme cascade (E1, E2, E3) in response to interferon stimulation. It also exists as a free secreted molecule that acts as a cytokine, modulating immune responses. ISG15 plays a key role in antiviral immunity, DNA damage response, and protein quality control. Deficiency leads to enhanced interferon signaling due to USP18 instability, causing autoinflammatory and immunodeficiency phenotypes.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| ISG15 Knockout HEK293 Cell Line | EDJ-KQ2727 | Human | 9636 | Details Get a Quote |
| ISG15 Knockout A-549 Cell Line | EDJ-KQ23584 | Human | 9636 | Details Get a Quote |
| ISG15 Knockout HCT 116 Cell Line | EDJ-KQ23585 | Human | 9636 | Details Get a Quote |
| ISG15 Knockout HeLa Cell Line | EDJ-KQ23586 | Human | 9636 | Details Get a Quote |
| ISG15 Knockout MDA-MB-231 Cell Line | EDC90452 | Human | 9636 | Details Get a Quote |
Displaying Records 1 To 5 Of 5 Records
