Alt. symbols: G1P2 | IFI15 | UCRP

Approved name: ISG15 ubiquitin like modifier
Alt. names: interferon, alpha-inducible protein (clone IFI-15K)

Location: 1p36.33: 1001138 - 1014540 (+)
Gene type: protein_coding, 3 transcripts.

Scores: LoFtool: 0.501000 | pLI: 0.00984781 | LOEUF: 1.691

HGNC: 4053

NCBI: 9636, RefSeq: NG_033033.2

Ensembl: ENSG00000187608.10

LRG_1231 | Status: public

OMIM: 147571

Expression | ProteinAtlas

Gene Ontology (GO)

• Molecular function: protein tag activity [GO:0031386]; structural constituent of ribosome [GO:0003735]; ubiquitin protein ligase binding [GO:0031625]
• Cell component: cytoplasm [GO:0005737]; nucleus [GO:0005634]; cytosolic small ribosomal subunit [GO:0022627]
• Biological process: ISG15-protein conjugation [GO:0032020]; modification-dependent protein catabolic process [GO:0019941]

Normal function

ISG15 is a small ubiquitin-like protein strongly induced by type I IFNs (PMID: 1373138), viral (PMID: 11157743) and bacterial infections (PMID: 26259872), LPS (PMID: 11854279) and retinoic acid (PMID: 14976209). ISG15 can be covalently conjugated onto target host and viral proteins via a 3-step enzymatic cascade, though the purpose of this ISGylation is still largely unknown (PMID: 29769653). ISGylation does not appear to directly target proteins for proteasome-mediated degradation, but ISG15 can compete with ubiquitin for ubiquitin binding sites on a protein, thereby indirectly regulating protein degradation (PMID: 16424026, 12426315). In addition, unconjugated ISG15 has been reported to function as a cytokine, with roles in the induction of natural killer (NK) cell proliferation (PMID: 8552607), dendritic cell maturation (PMID: 12067988), and IFN production, and serving as a chemotactic factor for neutrophils (PMID: 12963022).

Dysfunction and disease

Patients with biallelic nonsense or frameshift mutations in ISG15, resulting in absent protein, present with a type I IFNopathy associated with autoimmunity and MSMD (Mendelian susceptibility to mycobacterial disease) [OMIM: 616126]. The initially identified 3 patients developed severe disseminated Mycobacterial disease in response to BCG vaccination and were retrospectively found to have intracranial calcifications on neuroimaging (PMID: 22859821), while an additional 3 siblings from a Chinese family showed idiopathic basal ganglia calcifications and variable seizure activity without evidence of MSMD (did not receive BCG vaccines) or other infection susceptibilities (PMID: 25307056). Patients showed constitutive and strongly upregulated peripheral blood ISGs and the 3 patients with epileptic activity also had autoantibody levels higher than seen in age-matched controls. Zhang et al. (2015) showed that the absence of ISG15 essentially created a functional defect in USP18, a potent negative regulator of IFN-α/β signaling, and that failure of intracellular USP18 accumulation in patient cells resulted in their enhanced and amplified IFN-α/β signaling (PMID: 25307056). [Load More]