ISG15

Summary

ISG15 (ISG15 ubiquitin like modifier, HGNC:4053) is a protein-coding gene on chromosome 1p36.33, encoding Ubiquitin-like protein ISG15 (P05161). Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein.

The protein encoded by this gene is a ubiquitin-like protein that is conjugated to intracellular target proteins upon activation by interferon-alpha and interferon-beta. Several functions have been ascribed to the encoded protein, including chemotactic activity towards neutrophils, direction of ligated target proteins to intermediate filaments, cell-to-cell signaling, and antiviral activity during viral infections. While conjugates of this protein have been found to be noncovalently attached to intermediate filaments, this protein is sometimes secreted.

Source: NCBI Gene 9636 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 161 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 13
• Druggable target: yes
• MANE Select transcript: NM_005101

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4053
Approved symbol	ISG15
Name	ISG15 ubiquitin like modifier
Location	1p36.33
Locus type	gene with protein product
Status	Approved
Aliases	IFI15, UCRP
Ensembl gene	ENSG00000187608
Ensembl biotype	protein_coding
OMIM	147571
Entrez	9636

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000624652, ENST00000624697, ENST00000649529, ENST00000944242

RefSeq mRNA: 1 — MANE Select: NM_005101 NM_005101

CCDS: CCDS6

Canonical transcript exons

ENST00000649529 — 2 exons

Exon	Start	End
ENSE00001480799	1013984	1014540
ENSE00003831768	1013497	1013576

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 99.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 150.2536 / max 13219.0374, expressed in 1805 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47	149.8137	1800
45	0.2309	69
44	0.2090	85

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
decidua	UBERON:0002450	99.06	gold quality
periodontal ligament	UBERON:0008266	98.34	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	98.31	gold quality
granulocyte	CL:0000094	97.68	gold quality
amniotic fluid	UBERON:0000173	95.98	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.85	gold quality
trigeminal ganglion	UBERON:0001675	95.82	gold quality
stromal cell of endometrium	CL:0002255	95.68	gold quality
leukocyte	CL:0000738	95.66	gold quality
monocyte	CL:0000576	95.61	gold quality
mononuclear cell	CL:0000842	95.53	gold quality
amygdala	UBERON:0001876	95.40	gold quality
thymus	UBERON:0002370	95.30	gold quality
apex of heart	UBERON:0002098	95.01	gold quality
pericardium	UBERON:0002407	94.47	gold quality
blood	UBERON:0000178	93.29	gold quality
spleen	UBERON:0002106	93.27	gold quality
right coronary artery	UBERON:0001625	93.22	gold quality
right lobe of liver	UBERON:0001114	92.83	gold quality
putamen	UBERON:0001874	92.77	gold quality
descending thoracic aorta	UBERON:0002345	92.53	gold quality
right lung	UBERON:0002167	92.51	gold quality
duodenum	UBERON:0002114	92.20	gold quality
dorsal root ganglion	UBERON:0000044	92.14	gold quality
popliteal artery	UBERON:0002250	92.13	gold quality
tibial artery	UBERON:0007610	92.12	gold quality
vermiform appendix	UBERON:0001154	91.95	gold quality
aorta	UBERON:0000947	91.94	gold quality
hypothalamus	UBERON:0001898	91.91	gold quality
ascending aorta	UBERON:0001496	91.78	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 14.

Experiment	Marker?	Max mean expression
E-MTAB-9435	yes	7745.31
E-MTAB-8559	yes	4734.92
E-MTAB-7052	yes	4100.63
E-MTAB-10662	yes	4013.24
E-GEOD-139324	yes	3572.28
E-MTAB-9467	yes	3059.53
E-GEOD-149689	yes	2100.20
E-HCAD-8	yes	1291.69
E-CURD-95	yes	1202.33
E-CURD-85	yes	992.77
E-MTAB-6701	yes	41.10
E-MTAB-9388	yes	11.53
E-GEOD-137537	yes	6.02
E-HCAD-13	no	4092.84
E-GEOD-99795	no	859.59

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF3, IRF7, PTPN22, REL, SIRT6, STAT1

Literature-anchored findings (GeneRIF, showing 40)

• The ISG15 gene contains a unique interferon-stimulated response element that enables the binding and recruiting not only of interferon regulatory factors but also of PU.1. (PMID:12055236)
• Interferon stimulated gene 15 constitutively produced by melanoma cells induces e-cadherin expression on human dendritic cells. (PMID:12067988)
• RA treatment of APL and other RA-responsive leukemic cells induced expression of UBE1L and ISG15 as well as intracellular ISG15 conjugates. A physical association was found between UBE1L and ISG15 in vivo. (PMID:14976209)
• Quantitative-PCR and Northern analysis confirmed down-regulation of UCRP and UBE2L6 with BRCA2 knockdown, respectively. (PMID:15670748)
• ISG15 is induced by camptothecin in human tumor cells (PMID:15684817)
• The three-dimensional structure of recombinant ISG15C78S was determined at 2.4-A resolution.The docking model predicts side-chain interactions that presumably define the specificity between the ubiquitin and ISG15 ligation pathways (PMID:15917233)
• ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. (PMID:16009940)
• identify Lys92 as the only ISG15 modification site in Ubc13, which is the first report about the ISG15 modification site (PMID:16122702)
• These data indicate that ISGylation targets proteins found in several fundamentally important cellular pathways and will contribute to understanding the physiologic role of interferon-induced ISG15 and ISG15 conjugation. (PMID:16139798)
• results suggest that the ISG15 pathway, which is deregulated during tumorigenesis, negatively regulates the ubiquitin/proteasome pathway by interfering with protein polyubiquitination/degradation (PMID:16424026)
• isolated ISG15-modified and unmodified UbcH6 proteins, and analyzed their abilities to form thioester intermediates with ubiquitin (PMID:16428300)
• ISG15 is the critical component in IFN-mediated inhibition of HIV-1 release (PMID:16434471)
• Higher levels of ISG15 protein is associated with muscle-invasive bladder cancer (PMID:16641915)
• Four candidate target proteins were demonstrated to be ISGylated in UBE1L- and UbcH8-dependent manners (PMID:16884686)
• Efp protein could be conjugated with not only ubiquitin but also ISG15. (PMID:17069755)
• review evidence of a role for ISG15 as an endogenous tumor suppressor that, when dysregulated in malignant cells, can be subverted to promote oncogenesis (PMID:17097911)
• Thus we propose that autoISGylation of EFP negatively regulates its ISG15 E3 ligase activity for 14-3-3sigma. (PMID:17222803)
• ISGylation (by ISG15) of 4EHP may play an important role in cap structure-dependent translation control in immune responses. (PMID:17289916)
• ISG15 is a newcomer among ubiquitin-like molecules and utilizes the conjugating but also the deconjugating machinery of its more established relative ubiquitin. (PMID:17653289)
• Our results demonstrate that SARS-CoV PLpro can differentiate between ubiquitin-like modifiers sharing a common C-terminal sequence, and that the debranching activity of the PLpro is linkage type selective. (PMID:17692280)
• a mechanistically novel function of ISG15 in the enhancement of the innate anti-viral response through specific inhibition of Nedd4 Ub-E3 activity (PMID:18287095)
• These data provide evidence of antiviral activity of ISG15 against Ebola virus and suggest a mechanism of action involving disruption of Nedd4 function and subsequent ubiquitination of VP40. (PMID:18305167)
• N-terminal ubiquitin-like domain of ISG15 mainly functions in the ligation step and Influenza B virus NS1 protein inhibits ISGylation by competing with E3 ligases for binding to the N-terminal domain (PMID:18356159)
• These results suggest that ISG15, which interferes with proteasome-mediated repair of TOP1-DNA covalent complexes, is a potential tumor biomarker. (PMID:18566215)
• Ube1L was required for transfer of ISG15 to UbcH8 and for binding of Ube1L to UbcH8 (PMID:18583345)
• nitrosylation of ISG15 enhances target protein ISGylation (PMID:18606809)
• ISG15 is overexpressed in breast carcinoma cells compared with normal breast tissue, both at the RNA and protein level (PMID:18627608)
• expression of the ISG15 system suppresses NF-kappaB activation (PMID:19043203)
• Kinetic analysis revealed that mutation of arginine 153 to alanine (R153A) in ISG15 ablated hISG15-hUbE1L binding and transthiolation of UbcH8. (PMID:19073728)
• UBE1L-ISG15 preferentially inhibits cyclin D1 in lung cancer (PMID:19074853)
• Inhibition of influenza A virus gene expression by ISG15 conjugation in human cells is sufficient to result in inhibition of virus replication at early times of infection. (PMID:19357168)
• regulates immune response. (review) (PMID:19378789)
• study describes the modulation of androgen receptor expression by ISGylation components, which affects the proliferation of prostate cancer cells, thereby providing evidence for a novel function of the ISGylation system in malignant transformation (PMID:19430494)
• These results reveal a novel function for ISG15 in the regulation of the IFN-alpha pathway and its antihepatitis C effect. (PMID:19656964)
• ISG15 promotes hepatitis C virus production. (PMID:19846672)
• ISG15 is involved in cell growth and survival of prostate cancer (PMID:19956859)
• Data demonstrated that ISG15 is one of the genes associated with intrinsic gemcitabine sensitivity. (PMID:19959962)
• ISG15 over-expression in human medulloblastoma cells significantly reduced the Japanese encephalitis virus -induced cytopathic effect and inhibited virus replication by reducing the viral titers and genomes. (PMID:20035788)
• NS1B protein exhibits species-specific binding; it binds human and non-human primate ISG15 but not mouse or canine ISG15 (PMID:20093371)
• NS1 protein of influenza A virus (NS1A protein), an essential, multifunctional protein, is ISG15 modified in virus-infected cells. (PMID:20133869)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	isg15	ENSDARG00000086374
mus_musculus	Isg15	ENSMUSG00000035692
rattus_norvegicus	Isg15	ENSRNOG00000069527

Paralogs (10): UBL4A (ENSG00000102178), NEDD8 (ENSG00000129559), RPS27A (ENSG00000143947), UBC (ENSG00000150991), UBB (ENSG00000170315), ZFAND4 (ENSG00000172671), UBL4B (ENSG00000186150), ANKUB1 (ENSG00000206199), UBD (ENSG00000213886), UBA52 (ENSG00000221983)

Protein

Protein identifiers

Ubiquitin-like protein ISG15 — P05161 (reviewed: P05161)

Alternative names: Interferon-induced 15 kDa protein, Interferon-induced 17 kDa protein, Ubiquitin cross-reactive protein

All UniProt accessions (3): A0A096LNZ9, A0A096LPJ4, P05161

UniProt curated annotations — full annotation on UniProt →

Function. Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein. Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Isgylation of the viral sensor IFIH1/MDA5 promotes IFIH1/MDA5 oligomerization and triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses. Can also isgylate: EIF2AK2/PKR which results in its activation, RIGI which inhibits its function in antiviral signaling response, EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity, UBE2N and UBE2E1 which negatively regulates their activity, IRF3 which inhibits its ubiquitination and degradation and FLNB which prevents its ability to interact with the upstream activators of the JNK cascade thereby inhibiting IFNA-induced JNK signaling. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A, HIV-1 and Ebola virus. Restricts HIV-1 and ebola virus via disruption of viral budding. Inhibits the ubiquitination of HIV-1 Gag and host TSG101 and disrupts their interaction, thereby preventing assembly and release of virions from infected cells. Inhibits Ebola virus budding mediated by the VP40 protein by disrupting ubiquitin ligase activity of NEDD4 and its ability to ubiquitinate VP40. ISGylates influenza A virus NS1 protein which causes a loss of function of the protein and the inhibition of virus replication. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity. The secreted form acts through the integrin ITGAL/ITGB2 receptor to initiate activation of SRC family tyrosine kinases including LYN, HCK and FGR which leads to secretion of IFNG and IL10; the interaction is mediated by ITGAL.

Subunit / interactions. Homodimer; disulfide-linked. Interacts with, and is conjugated to its targets by UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme). Interacts with NEDD4. Interacts with PARP12; this interaction inhibits PINK1/Parkin-dependent mitophagy. (Microbial infection) Interacts with vaccinia virus protein E3. (Microbial infection) Interaction with influenza B NS1 protein inhibits its conjugation. (Microbial infection) Interacts (via C-terminus) with Crimean-Congo hemorrhagic fever virus (CCHFV) RNA-directed RNA polymerase L (via N-terminus); the deISGylase activity of the viral protein interferes with antiviral signaling pathways mediated by NF-kappaB and IRF signalings. (Microbial infection) Interacts with human cytomegalovirus protein UL26; this interaction inhibits global protein ISGylation.

Subcellular location. Cytoplasm. Secreted.

Tissue specificity. Detected in lymphoid cells, striated and smooth muscle, several epithelia and neurons. Expressed in neutrophils, monocytes and lymphocytes. Enhanced expression seen in pancreatic adenocarcinoma, endometrial cancer, and bladder cancer, as compared to non-cancerous tissue. In bladder cancer, the increase in expression exhibits a striking positive correlation with more advanced stages of the disease.

Post-translational modifications. S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins. Induced as an inactive, precursor protein that is cleaved by specific proteases to expose the C-terminal diglycine (LRLRGG) motif. This motif is essential not only for its conjugation to substrates but also for its recognition by the relevant processing proteases.

Disease relevance. Immunodeficiency 38, with basal ganglia calcification (IMD38) [MIM:616126] A primary immunodeficiency predisposing individuals to severe clinical disease upon infection with weakly virulent mycobacteria, including Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccines. Patients are also susceptible to Salmonella and Mycobacterium tuberculosis infections. Affected individuals have intracranial calcification. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Both the Ubiquitin-like 1 and Ubiquitin-like 2 domains are required for its efficient conjugation to cellular proteins. The two domains play different roles in the ISGylation pathway: Ubiquitin-like 2 domain is necessary for the first two steps allowing the linking of ISG15 to the E1 and E2 enzymes while Ubiquitin-like 1 domain is essential for the final, E3-mediated transfer of ISG15, from the E2 to the Lys of the target protein.

Induction. Strongly induced upon exposure to type I interferons, viruses, LPS, and other stresses, including certain genotoxic stresses.

RefSeq proteins (1): NP_005092* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR015496	Ubiquilin	Family
IPR019956	Ubiquitin_dom	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily

Pfam: PF00240

UniProt features (42 total): strand 15, mutagenesis site 7, helix 6, domain 2, initiator methionine 1, chain 1, cross-link 1, sequence variant 1, sequence conflict 1, propeptide 1, turn 1, region of interest 1, short sequence motif 1, site 1, modified residue 1, disulfide bond 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
6FFA	X-RAY DIFFRACTION	1.5
3PHX	X-RAY DIFFRACTION	1.6
3RT3	X-RAY DIFFRACTION	2.01
7S6P	X-RAY DIFFRACTION	2.15
3SDL	X-RAY DIFFRACTION	2.29
6BI8	X-RAY DIFFRACTION	2.29
3PSE	X-RAY DIFFRACTION	2.3
3R66	X-RAY DIFFRACTION	2.3
5W8U	X-RAY DIFFRACTION	2.41
1Z2M	X-RAY DIFFRACTION	2.5
9NN9	X-RAY DIFFRACTION	2.59
5TL6	X-RAY DIFFRACTION	2.62
5W8T	X-RAY DIFFRACTION	2.76
6XA9	X-RAY DIFFRACTION	2.9
7RBS	X-RAY DIFFRACTION	2.98
9ZFO	ELECTRON MICROSCOPY	3.05
8SE9	ELECTRON MICROSCOPY	3.2
8SEB	ELECTRON MICROSCOPY	3.24
8SV8	ELECTRON MICROSCOPY	3.38
8SEA	ELECTRON MICROSCOPY	3.4
8OIF	ELECTRON MICROSCOPY	3.5
2HJ8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05161-F1	86.58	0.43

Antibody-complex structures (SAbDab): 1 — 9NN9

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 153 (interacts with activating enzyme)

Post-translational modifications (2): 157, 78

Disulfide bonds (1): 78

Mutagenesis-validated functional residues (7):

Position	Phenotype
44	does not affect isg15 signaling, interaction with itgal or activation of src family tyrosine kinases.
83	does not affect isg15 signaling, interaction with itgal or activation of src family tyrosine kinases.
96	reduces isg15 signaling. strongly reduces isg15 signaling and abolishes interaction with itgal and activation of src fam
99	strongly reduces isg15 signaling and abolishes interaction with itgal.
101	strongly reduces isg15 signaling and abolishes interaction with itgal and activation of src family tyrosine kinases.
102	reduces isg15 signaling. strongly reduces isg15 signaling and abolishes interaction with itgal and activation of src fam
103	strongly reduces isg15 signaling and abolishes interaction with itgal.

Function

Pathways and Gene Ontology

Reactome pathways

26 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-168276	NS1 Mediated Effects on Host Pathways
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta
R-HSA-5656169	Termination of translesion DNA synthesis
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-9833110	RSV-host interactions
R-HSA-9833482	PKR-mediated signaling
R-HSA-9909505	Modulation of host responses by IFN-stimulated genes
R-HSA-110313	Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template
R-HSA-1169410	Antimicrobial mechanism of IFN-stimulated genes
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168255	Influenza Infection
R-HSA-168256	Immune System
R-HSA-5663205	Infectious disease
R-HSA-73893	DNA Damage Bypass
R-HSA-73894	DNA Repair
R-HSA-913531	Interferon Signaling
R-HSA-9679506	SARS-CoV Infections
R-HSA-9694516	SARS-CoV-2 Infection
R-HSA-9705683	SARS-CoV-2-host interactions
R-HSA-9820952	Respiratory Syncytial Virus Infection Pathway
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 626 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, BROWNE_HCMV_INFECTION_4HR_UP, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, MODULE_52, MODULE_92, WALLACE_PROSTATE_CANCER_RACE_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, JI_RESPONSE_TO_FSH_UP, REACTOME_INNATE_IMMUNE_SYSTEM, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_POSITIVE_REGULATION_OF_ERYTHROCYTE_DIFFERENTIATION, GOBP_MYELOID_CELL_HOMEOSTASIS, MODULE_169

GO Biological Process (23): integrin-mediated signaling pathway (GO:0007229), response to virus (GO:0009615), modification-dependent protein catabolic process (GO:0019941), positive regulation of bone mineralization (GO:0030501), negative regulation of protein ubiquitination (GO:0031397), ISG15-protein conjugation (GO:0032020), positive regulation of protein oligomerization (GO:0032461), regulation of type II interferon production (GO:0032649), positive regulation of interferon-beta production (GO:0032728), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-10 production (GO:0032733), response to type I interferon (GO:0034340), defense response to bacterium (GO:0042742), negative regulation of viral genome replication (GO:0045071), innate immune response (GO:0045087), positive regulation of erythrocyte differentiation (GO:0045648), defense response to virus (GO:0051607), negative regulation of type I interferon-mediated signaling pathway (GO:0060339), protein localization to mitochondrion (GO:0070585), immune system process (GO:0002376), regulation of immune system process (GO:0002682), response to bacterium (GO:0009617), positive regulation of multicellular organismal process (GO:0051240)

GO Molecular Function (4): integrin binding (GO:0005178), protein tag activity (GO:0031386), ubiquitin protein ligase binding (GO:0031625), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Interferon Signaling	3
Antimicrobial mechanism of IFN-stimulated genes	2
Immune System	2
Influenza Infection	1
Innate Immune System	1
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1
SARS-CoV-2-host interactions	1
Respiratory Syncytial Virus Infection Pathway	1
DNA Damage Bypass	1
Viral Infection Pathways	1
Disease	1
DNA Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
type II interferon production	2
positive regulation of cytokine production	2
defense response	2
cell surface receptor signaling pathway	1
response to other organism	1
protein catabolic process	1
protein modification process	1
modification-dependent macromolecule catabolic process	1
bone mineralization	1
regulation of bone mineralization	1
positive regulation of ossification	1
positive regulation of biomineral tissue development	1
protein ubiquitination	1
regulation of protein ubiquitination	1
negative regulation of protein modification by small protein conjugation or removal	1
protein modification by small protein conjugation	1
positive regulation of protein-containing complex assembly	1
regulation of protein oligomerization	1
protein complex oligomerization	1
regulation of cytokine production	1
positive regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
regulation of type II interferon production	1
interleukin-10 production	1
regulation of interleukin-10 production	1
response to cytokine	1
innate immune response	1
response to bacterium	1
viral genome replication	1
regulation of viral genome replication	1
negative regulation of viral process	1
immune response	1
defense response to symbiont	1
erythrocyte differentiation	1
positive regulation of myeloid cell differentiation	1
regulation of erythrocyte differentiation	1
response to virus	1
negative regulation of cytokine-mediated signaling pathway	1

Protein interactions and networks

STRING

5502 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ISG15	USP18	Q9UMW8	959
ISG15	RIGI	O95786	953
ISG15	HERC5	Q9UII4	942
ISG15	STAT1	P42224	935
ISG15	IFIH1	Q9BYX4	935
ISG15	IFIT1	P09914	934
ISG15	MX1	P20591	932
ISG15	OAS1	P00973	923
ISG15	OASL	Q15646	906
ISG15	UBA7	P41226	903
ISG15	RSAD2	Q8WXG1	890
ISG15	IRF3	Q14653	888
ISG15	IFNB1	P01574	880
ISG15	MX2	P20592	879
ISG15	IFIT3	O14879	879

IntAct

127 interactions, top by confidence:

A	B	Type	Score
rep	ISG15	psi-mi:“MI:0407”(direct interaction)	0.910
rep	ISG15	psi-mi:“MI:0194”(cleavage reaction)	0.910
rep	ISG15	psi-mi:“MI:0570”(protein cleavage)	0.910
ISG15	rep	psi-mi:“MI:0194”(cleavage reaction)	0.910
rep	ISG15	psi-mi:“MI:0914”(association)	0.910
rep	ISG15	psi-mi:“MI:0915”(physical association)	0.910
rep	ISG15	psi-mi:“MI:0195”(covalent binding)	0.910
ISG15	UBA7	psi-mi:“MI:0915”(physical association)	0.890
UBA7	ISG15	psi-mi:“MI:0915”(physical association)	0.890
UBA7	ISG15	psi-mi:“MI:0407”(direct interaction)	0.890
UBA7	ISG15	psi-mi:“MI:0914”(association)	0.890
USP18	ISG15	psi-mi:“MI:0915”(physical association)	0.870
ISG15	USP18	psi-mi:“MI:0915”(physical association)	0.870
ISG15	L	psi-mi:“MI:0407”(direct interaction)	0.740

BioGRID (644): ISG15 (Affinity Capture-Western), ISG15 (Two-hybrid), USP18 (Two-hybrid), ISG15 (Affinity Capture-Western), ISG15 (Affinity Capture-Western), ISG15 (Affinity Capture-Western), ISG15 (Reconstituted Complex), ISG15 (Reconstituted Complex), ISG15 (Affinity Capture-MS), ISG15 (Affinity Capture-MS), ISG15 (Affinity Capture-MS), ISG15 (Affinity Capture-MS), USP18 (Two-hybrid), ISG15 (Two-hybrid), ISG15 (Affinity Capture-MS)

ESM2 similar proteins: A1A5Z3, A4QND0, A5WVX1, A6QLY4, A9UMP7, B5X5B4, B5X9S9, B5XFI8, C0HAV3, C1BGZ8, C1BHN7, C1BXU5, C3KHF2, O00329, O02741, O35904, O88512, P05161, P54729, Q0D261, Q14AI0, Q19KS6, Q28DG7, Q4R720, Q5E951, Q5FW14, Q5R8F5, Q5U378, Q5XIR9, Q5ZJI9, Q64339, Q66HA5, Q66I84, Q6I7R3, Q6NTR1, Q6NU25, Q6PBQ2, Q7T0X5, Q7ZWB2, Q8K1A6

Diamond homologs: C4YP88, O02741, P05161, P05759, P0C016, P0C224, P0C273, P0C275, P0C276, P0C8R3, P0CG47, P0CG48, P0CG49, P0CG50, P0CG51, P0CG53, P0CG54, P0CG55, P0CG60, P0CG61, P0CG62, P0CG63, P0CG64, P0CG65, P0CG66, P0CG67, P0CG68, P0CG69, P0CG70, P0CG71, P0CG72, P0CG73, P0CG74, P0CG75, P0CG82, P0CG83, P0CG84, P0CG85, P0CH04, P0CH05

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 46 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
TRAF6 mediated IRF7 activation	12	134.3×	6e-22
Regulation of IFNA/IFNB signaling	10	129.2×	3e-18
Evasion by RSV of host interferon responses	12	115.2×	3e-21
Interferon alpha/beta signaling	11	49.3×	4e-15
SARS-CoV-2 activates/modulates innate and adaptive immune responses	12	31.5×	3e-14
ISG15 antiviral mechanism	7	30.9×	4e-08
Factors involved in megakaryocyte development and platelet production	9	17.6×	3e-08

GO biological processes:

GO term	Partners	Fold	FDR
B cell activation involved in immune response	9	237.0×	1e-18
natural killer cell activation involved in immune response	9	223.0×	2e-18
T cell activation involved in immune response	9	158.0×	7e-17
response to exogenous dsRNA	9	118.5×	1e-15
type I interferon-mediated signaling pathway	12	103.2×	8e-20
cellular response to virus	14	70.2×	1e-20
humoral immune response	9	63.2×	6e-13
antiviral innate immune response	5	28.5×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

161 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	75
Likely benign	61
Benign	11

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
145356	GRCh38/hg38 1p36.33-36.32(chr1:844353-3487877)x1	Pathogenic
161455	NM_005101.4(ISG15):c.339dup (p.Leu114fs)	Pathogenic
183381	NM_005101.4(ISG15):c.163C>T (p.Gln55Ter)	Pathogenic
161454	NM_005101.4(ISG15):c.379G>T (p.Glu127Ter)	Likely pathogenic

SpliceAI

101 predictions. Top by Δscore:

Variant	Effect	Δscore
1:1013577:G:GA	donor_loss	1.0000
1:1013577:G:GG	donor_gain	1.0000
1:1013578:T:A	donor_loss	1.0000
1:1013575:TG:T	donor_gain	0.9900
1:1013576:GG:G	donor_gain	0.9900
1:1013980:GCAGG:G	acceptor_loss	0.9900
1:1013981:CAGGG:C	acceptor_loss	0.9900
1:1013982:A:C	acceptor_loss	0.9900
1:1013982:AG:A	acceptor_gain	0.9900
1:1013983:G:GC	acceptor_loss	0.9900
1:1013983:GG:G	acceptor_gain	0.9900
1:1013983:GGGCT:G	acceptor_gain	0.9900
1:1013982:A:AG	acceptor_gain	0.9800
1:1013983:G:GG	acceptor_gain	0.9800
1:1013983:GGGC:G	acceptor_gain	0.9700
1:1013572:CCATG:C	donor_gain	0.9500
1:1013574:ATG:A	donor_gain	0.9500
1:1013529:A:AG	donor_gain	0.9300
1:1013530:G:GG	donor_gain	0.9300
1:1013982:AGG:A	acceptor_gain	0.9000
1:1013983:GGG:G	acceptor_gain	0.9000
1:1013573:CATG:C	donor_gain	0.8900
1:1013975:C:CA	acceptor_gain	0.8800
1:1014055:G:T	acceptor_gain	0.8800
1:1013576:GGT:G	donor_gain	0.8700
1:1013577:GTA:G	donor_gain	0.8700
1:1013697:GTTC:G	donor_gain	0.8700
1:1013698:TTCT:T	donor_gain	0.8700
1:1013979:T:TA	acceptor_gain	0.8700
1:1013574:ATGGT:A	donor_gain	0.8500

AlphaMissense

1062 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:1014304:G:C	K108N	0.993
1:1014304:G:T	K108N	0.993
1:1014192:T:A	V71D	0.987
1:1014300:T:C	L107P	0.976
1:1014237:T:A	V86E	0.975
1:1014231:T:C	I84T	0.973
1:1014356:T:C	F126L	0.972
1:1014358:C:A	F126L	0.972
1:1014358:C:G	F126L	0.972
1:1014231:T:G	I84S	0.969
1:1014423:T:A	V148E	0.969
1:1014231:T:A	I84N	0.968
1:1014101:T:C	F41L	0.966
1:1014103:C:A	F41L	0.966
1:1014103:C:G	F41L	0.966
1:1014351:T:C	L124P	0.965
1:1014344:T:C	F122L	0.964
1:1014346:C:A	F122L	0.964
1:1014346:C:G	F122L	0.964
1:1014067:G:C	K29N	0.961
1:1014067:G:T	K29N	0.961
1:1014063:T:C	L28P	0.957
1:1014303:A:C	K108T	0.957
1:1014266:T:G	Y96D	0.952
1:1014198:T:C	L73P	0.949
1:1014312:T:A	V111E	0.945
1:1014351:T:A	L124Q	0.945
1:1014075:T:G	I32S	0.944
1:1014000:T:A	V7E	0.943
1:1014243:A:T	N88I	0.939

dbSNP variants (sampled 300 via entrez): RS1000064079 (1:1012829 T>C), RS1002806730 (1:1011588 C>G), RS1002915990 (1:1014411 C>T), RS1003720479 (1:1012027 C>A), RS1005779578 (1:1013422 G>T), RS1006528054 (1:1014913 T>C), RS1008188915 (1:1013922 G>A), RS1008572188 (1:1012976 A>G), RS1009039337 (1:1013244 G>T), RS1010946405 (1:1014188 A>G), RS1011082220 (1:1014910 G>T), RS1012947525 (1:1011984 C>T), RS1013005860 (1:1013933 G>C,T), RS1013387249 (1:1014142 G>A), RS1013960232 (1:1012885 C>T)

Disease associations

OMIM: gene MIM:147571 | disease phenotypes: MIM:616126

GenCC curated gene-disease

Disease	Classification	Inheritance
Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency	Strong	Autosomal recessive

Mondo (1): Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency (MONDO:0014502)

Orphanet (1): Mendelian susceptibility to mycobacterial diseases due to complete ISG15 deficiency (Orphanet:319563)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0002135	Basal ganglia calcification
HP:0002716	Lymphadenopathy
HP:0002721	Immunodeficiency
HP:0003593	Infantile onset
HP:0004429	Recurrent viral infections
HP:0011274	Recurrent mycobacterial infections
HP:0012759	Neurodevelopmental abnormality
HP:0020086	BCGitis
HP:0031691	Severe viral infection
HP:0034751	Inguinal lymphadenopathy
HP:0034752	Axillary lymphadenopathy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_7	Blood protein levels	2.000000e-12

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5482992 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.72	EC50	1900	nM	CHEMBL5410606

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[8-chloro-3-[2-[(2-methoxyphenyl)methylamino]-2-oxoethyl]-4-oxoquinazolin-2-yl]propanoic acid	2010558: Antagonist activity at N-terminal NanoLuc-tagged HDAC6 (unknown origin)/N-terminal HaloTag-tagged ISGI5 /(unknown origin) transfected in human HEK293T cells assessed as inhibition of protein-protein interaction preincubated for 240 min followed by Nano-Glo substrate addition and measured for 10 mins by NanoBRET assay	ec50	1.9000	uM

CTD chemical–gene interactions

115 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases expression, decreases expression, affects acetylation, affects methylation	5
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression, decreases reaction	5
Tretinoin	affects expression, increases expression	5
Cisplatin	increases expression, affects expression, affects cotreatment	4
Lipopolysaccharides	increases expression, decreases reaction	4
Air Pollutants	decreases expression, increases abundance	3
Estradiol	affects cotreatment, increases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	3
Valproic Acid	affects expression, increases expression	3
Aflatoxin B1	increases expression, affects expression	3
Dexamethasone	affects cotreatment, decreases expression, decreases reaction	2
Fluorouracil	increases expression	2
Formaldehyde	decreases expression, increases expression	2
Nickel	increases expression	2
Rotenone	decreases expression, increases expression	2
Smoke	decreases expression, increases abundance	2
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression, decreases reaction	2
Cyclosporine	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, decreases expression	1
HZ-6d compound	decreases expression	1
PAM2-CSK4	affects reaction, increases expression, decreases reaction	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
chlorophyllin	decreases reaction, increases expression	1
lipoteichoic acid	increases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, decreases expression, affects cotreatment	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5364126	Binding	Antagonist activity at N-terminal NanoLuc-tagged HDAC6 (unknown origin)/N-terminal HaloTag-tagged ISGI5 /(unknown origin) transfected in human HEK293T cells assessed as inhibition of protein-protein interaction preincubated for 240 min foll	Discovery and Characterization of a Chemical Probe Targeting the Zinc-Finger Ubiquitin-Binding Domain of HDAC6. — J Med Chem

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 2 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4CX	MHHi001-A-3	Induced pluripotent stem cell	Female
CVCL_A4CY	MHHi001-A-4	Induced pluripotent stem cell	Female
CVCL_D7SJ	Ubigene A-549 ISG15 KO	Cancer cell line	Male
CVCL_E0FD	Ubigene HeLa ISG15 KO	Cancer cell line	Female
CVCL_E1D1	Ubigene THP-1 ISG15 KO	Cancer cell line	Male
CVCL_ST08	HAP1 ISG15 (-) 1	Cancer cell line	Male
CVCL_ST09	HAP1 ISG15 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.