USP18

Summary

USP18 (ubiquitin specific peptidase 18, HGNC:12616) is a protein-coding gene on chromosome 22q11.21, encoding Ubl carboxyl-terminal hydrolase 18 (Q9UMW8). Interferon-induced ISG15-specific protease that plays a crucial role for maintaining a proper balance of ISG15-conjugated proteins in cells. It is a selective cancer dependency (DepMap: 27.9% of cell lines).

The protein encoded by this gene belongs to the ubiquitin-specific proteases (UBP) family of enzymes that cleave ubiquitin from ubiquitinated protein substrates. It is highly expressed in liver and thymus, and is localized to the nucleus. This protein efficiently cleaves only ISG15 (a ubiquitin-like protein) fusions, and deletion of this gene in mice results in a massive increase of ISG15 conjugates in tissues, indicating that this protein is a major ISG15-specific protease. Mice lacking this gene are also hypersensitive to interferon, suggesting a function of this protein in downregulating interferon responses, independent of its isopeptidase activity towards ISG15.

Source: NCBI Gene 11274 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pseudo-TORCH syndrome 2 (Definitive, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 88 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 27.9% of screened cell lines
• MANE Select transcript: NM_017414

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12616
Approved symbol	USP18
Name	ubiquitin specific peptidase 18
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000184979
Ensembl biotype	protein_coding
OMIM	607057
Entrez	11274

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 14 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000215794, ENST00000699060, ENST00000699061, ENST00000699062, ENST00000715585, ENST00000896317, ENST00000896318, ENST00000896319, ENST00000896320, ENST00000896321, ENST00000896322, ENST00000896323, ENST00000896324, ENST00000896325, ENST00000912381, ENST00000912382, ENST00000949086

RefSeq mRNA: 1 — MANE Select: NM_017414 NM_017414

CCDS: CCDS13752

Canonical transcript exons

ENST00000215794 — 11 exons

Exon	Start	End
ENSE00000650514	18161790	18161935
ENSE00001325029	18157558	18157820
ENSE00001598455	18167255	18167334
ENSE00001648315	18173793	18173842
ENSE00001651074	18173150	18173281
ENSE00001714040	18169844	18169939
ENSE00001757748	18167890	18168036
ENSE00001786824	18160172	18160268
ENSE00003975562	18150170	18150222
ENSE00004027297	18170753	18170920
ENSE00004027299	18176772	18177397

Expression profiles

Bgee: expression breadth ubiquitous, 135 present calls, max score 84.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.7523 / max 936.4674, expressed in 1250 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191021	12.8671	998
191020	1.3756	305
191018	0.9139	482
191019	0.5956	159

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.15	gold quality
left testis	UBERON:0004533	82.87	gold quality
right testis	UBERON:0004534	82.63	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.07	gold quality
testis	UBERON:0000473	81.94	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.93	gold quality
liver	UBERON:0002107	80.29	gold quality
adipose tissue	UBERON:0001013	80.06	gold quality
lymph node	UBERON:0000029	79.75	gold quality
right lobe of liver	UBERON:0001114	79.25	gold quality
omental fat pad	UBERON:0010414	78.94	gold quality
islet of Langerhans	UBERON:0000006	78.83	gold quality
placenta	UBERON:0001987	78.73	gold quality
ventricular zone	UBERON:0003053	77.71	gold quality
right lobe of thyroid gland	UBERON:0001119	77.62	gold quality
right adrenal gland cortex	UBERON:0035827	77.50	gold quality
calcaneal tendon	UBERON:0003701	77.28	gold quality
left lobe of thyroid gland	UBERON:0001120	77.04	gold quality
right adrenal gland	UBERON:0001233	77.02	gold quality
apex of heart	UBERON:0002098	76.78	gold quality
thyroid gland	UBERON:0002046	76.70	gold quality
gall bladder	UBERON:0002110	76.56	gold quality
tibial nerve	UBERON:0001323	76.54	gold quality
thoracic mammary gland	UBERON:0005200	76.46	gold quality
upper lobe of left lung	UBERON:0008952	76.33	gold quality
fallopian tube	UBERON:0003889	76.27	gold quality
granulocyte	CL:0000094	76.23	gold quality
left adrenal gland	UBERON:0001234	76.06	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	75.94	gold quality
duodenum	UBERON:0002114	75.91	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7037	yes	665.99
E-ANND-3	yes	11.84
E-MTAB-4850	no	857.73
E-MTAB-8060	no	157.86

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF2, IRF3, IRF6, WT1

miRNA regulators (miRDB)

42 targeting USP18, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-5007-3P	99.51	68.14	1242
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-1843	98.97	66.07	838
HSA-MIR-4802-5P	98.97	66.26	833
HSA-MIR-520G-3P	98.91	67.38	1914
HSA-MIR-520H	98.91	67.38	1914

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 27.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• UBP43 protein levels are regulated by proteolysis via the SCFSkp2 ubiquitin ligase (PMID:15342634)
• Ubp43 deficiency increases the resistance to oncogenic transformation by BCR-ABL (PMID:17374743)
• Epstein-Barr virus independent dysregulation of UBP43 expression alters interferon-stimulated gene expression in Burkitt lymphoma (PMID:19551150)
• Findings suggest that USP18 may significantly limit operation of the extrinsic apoptotic pathway triggered by type I IFN and drugs. (PMID:20068173)
• Findings define the ubiquitin protease UBP43 as a novel candidate drug target for APL treatment. (PMID:20935222)
• a model in which Usp18 inhibition promotes up-regulation of miR-7, which in turn inhibits EGFR expression and the tumorigenic activity of cancer cells. (PMID:21592959)
• Inhibition of R. conorii-induced ISG15 by RNA interference results in significant increase in the extent of rickettsial replication, whereas UBP43 knockdown yields a reciprocal inhibitory effect. (PMID:22100648)
• the existence of an N-terminal truncated isoform of USP18, whose expression is controlled on translational level by two independent mechanisms providing translational flexibility (PMID:22170061)
• USP18 is up-regulated in liver samples of patients with chronic hepatitis C that did not respond to therapy, but not in patients with acute hepatitis C. (PMID:22677194)
• although UBP43 depletion can cause hypersensitivity to interferon-alpha/beta-mediated apoptosis in a broad range of cell types, the downstream pathway may vary depending on the cell type. (PMID:22683641)
• USP18 establishes the transcriptional and anti-proliferative interferon alpha/beta differential (PMID:22731491)
• A direct relationship was found between UBP43 and cyclin D1 (but not cyclin E) expression. (PMID:22752428)
• USP18 inhibition induces inflammation by increasing the STAT signaling and exacerbates IFN-induced beta cell apoptosis. (PMID:23152055)
• Usp18 upregulation was associated with Wilms Tumor. (PMID:23291318)
• USP18 expression levels induced by IFNbeta did not differ amongst multiple sclerosis patients carrying different rs2542109 genotypes (PMID:23700969)
• increased expression in the HIV+/HCV+ female patients group compared with HIV-/HCV+ and HIV+/HCV- groups (PMID:24955730)
• Dimerization of IFNAR1 and IFNAR2 and the limiting role of IFNAR1 binding affinity in complex assembly is modulated by USP18. (PMID:26008745)
• Data suggest that USP18 (Ubiquitin-like specific protease 18) sensitive cellular functions include activity of the peptide transporters PEPT1 and PEPT2. (PMID:26046984)
• USP18 negatively regulates NF-kappaB signaling by targeting TAK1 and NEMO for deubiquitination through distinct mechanisms. (PMID:26240016)
• findings show that multiple inflammatory stimuli can modulate interferon stimulated gene expression and thus inhibit hepatocyte interferon signaling via USP18 induction (PMID:27009955)
• results indicated that USP18 modulates the anti-HBV activity of IFN-F via activation of the JAK/STAT signaling pathway in Hepg2.2.15 cells. (PMID:27227879)
• These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies (PMID:27325888)
• We show that IRF-7 siRNA knockdown enhanced LPS-induced IL-10 production in human monocyte-derived macrophages, and USP-18 overexpression attenuated LPS-induced production of IL-10 in RAW264.7 cells. Quantitative PCR confirmed upregulation of USP18, USP41, IL10, and IRF7. An independent cohort confirmed LPS induction of USP41 and IL10 genes (PMID:27434537)
• High expression levels of USP18 in the muscles of dermatomyositis patients. (PMID:27605457)
• this study identified PTEN as a previously unrecognized substrate of the ISGylation post-translational modification pathway. The deconjugase USP18 serves as a novel regulator of PTEN stability. This indicates inhibition of ISGylation is therapeutically relevant in cancers. (PMID:27980214)
• USP18’s ISG15 specificity is mediated by a small interaction interface. (PMID:28165509)
• STAT2 recruits USP18 to the type I IFN receptor subunit IFNAR2 via its constitutive membrane-distal STAT2-binding site. (PMID:28165510)
• study preliminary elucidated the role of USP18 in hepatitis B virus replication and explored the potential key genes in USP18-mediated signaling pathway (PMID:28369997)
• These results demonstrate that virus-induced IFN-lambda4 potently blocks IFN-alpha signalling by inducing high protein levels of ISG15 and USP18. Moreover, the data clearly demonstrate that DAA therapy restores IFN-alpha responsiveness in HCV-infected cells. (PMID:28630501)
• that Ubiquitin-specific peptidase 18 directly bind to BCL2L1 and positively regulated its expression in hepatocellular carcinoma cells (PMID:28709980)
• associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance, and the inflammatory response (PMID:28718215)
• The structures of ubiquitin-specific protease 18 (USP18) and a USP18-Interferon-stimulated 15-KDa protein (ISG15) complex indicate the molecular basis of the specificity of the protease and its interaction with the type I interferon receptor [Review]. (PMID:28881486)
• The role of USP18 in breast cancer provides a novel insight into the clinical application of the USP18/AKT/Skp2 pathway. (PMID:29749454)
• The authors have found that USP18 has the novel ability to inhibit the antiviral function of p21 in differentiated THP-1 cells. USP18 enhanced reverse transcription of HIV-1 by downregulating p21 expression and upregulating intracellular dNTP levels. (PMID:30068654)
• In this review, we summarise our current knowledge of protease-dependent and -independent functions of USP18 and discuss the structural basis of its dual activity (PMID:30126853)
• USP18 and ISG15 coordinately impact on SKP2 and cell cycle progression. (PMID:30858391)
• We demonstrated that clinical outcome of IFN-alpha therapy in chronic hepatitis B patients is associated with the transcriptional response of USP18 to IFN-alpha in in vitro cultured PBMCs. (PMID:31074081)
• This work clarifies the function and consequences of p53 modification by ISG15 and implicates USP18 in HIV-1 infection and potentially in carcinogenesis. (PMID:31455647)
• The authors establish a direct role for type I IFN/USP18 signaling in the maintenance of total and virus-specific Memory CD4 T-cells and provide a new mechanism for the reduced survival of these populations during primary HIV-1 infection. (PMID:31658294)
• we observed increased USP18 and IL2RA expressions after one and six months of INH therapy and decreased IFNA, CCL4, and CXCL11 expressions after six months of LTBI treatment. These results might facilitate the use of mRNA expression as a tool for monitoring INH treatment and may have the potential for monitoring new alternative LTBI regimens. (PMID:31886294)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Usp18	ENSMUSG00000030107
rattus_norvegicus	Usp18	ENSRNOG00000037198

Paralogs (71): USP2 (ENSG00000036672), USP28 (ENSG00000048028), USP36 (ENSG00000055483), USP13 (ENSG00000058056), USP33 (ENSG00000077254), USP40 (ENSG00000085982), USP48 (ENSG00000090686), USP14 (ENSG00000101557), USP11 (ENSG00000102226), USP10 (ENSG00000103194), USP31 (ENSG00000103404), USP42 (ENSG00000106346), USP5 (ENSG00000111667), USP4 (ENSG00000114316), USP9Y (ENSG00000114374), USP34 (ENSG00000115464), USP35 (ENSG00000118369), USP45 (ENSG00000123552), USP22 (ENSG00000124422), USP9X (ENSG00000124486), USP6 (ENSG00000129204), USP29 (ENSG00000131864), USP26 (ENSG00000134588), USP30 (ENSG00000135093), USP15 (ENSG00000135655), USP37 (ENSG00000135913), USP44 (ENSG00000136014), USP20 (ENSG00000136878), USP8 (ENSG00000138592), USP3 (ENSG00000140455), USP21 (ENSG00000143258), USP43 (ENSG00000154914), USP25 (ENSG00000155313), USP16 (ENSG00000156256), USP24 (ENSG00000162402), USP1 (ENSG00000162607), USP49 (ENSG00000164663), USP38 (ENSG00000170185), USP50 (ENSG00000170236), USP47 (ENSG00000170242)

Protein

Protein identifiers

Ubl carboxyl-terminal hydrolase 18 — Q9UMW8 (reviewed: Q9UMW8)

Alternative names: 43 kDa ISG15-specific protease, ISG15-specific-processing protease, Ubl thioesterase 18

All UniProt accessions (3): A0A8V8TMN0, A0AAQ5BIJ4, Q9UMW8

UniProt curated annotations — full annotation on UniProt →

Function. Interferon-induced ISG15-specific protease that plays a crucial role for maintaining a proper balance of ISG15-conjugated proteins in cells. Regulates protein ISGylation by efficiently cleaving ISG15 conjugates linked via isopeptide bonds. Regulates T-cell activation and T-helper 17 (Th17) cell differentiation by deubiquitinating TAK1, likely to keep TAK1-TAB complexes in steady conditions. In turn, restricts activation of NF-kappa-B, NFAT, and JNK as well as expression of IL2 in T-cells after TCR activation. Acts as a molecular adapter with USP20 to promote innate antiviral response through deubiquitinating STING1. Involved also in the negative regulation of the inflammatory response triggered by type I interferon. Upon recruitment by STAT2 to the type I interferon receptor subunit IFNAR2 interferes with the assembly of the ternary interferon-IFNAR1-IFNAR2 complex and acts as a negative regulator of the type I interferon signaling pathway. Has enzymatic activity similar to isoform 1 and interferes with type I interferon signaling. Major deISGylation enzyme for nuclear proteins.

Subunit / interactions. Interacts with STAT2; the interaction is direct. Interacts with IFNAR2; indirectly via STAT2, it negatively regulates the assembly of the ternary interferon-IFNAR1-IFNAR2 complex and inhibits type I interferon signaling. Interacts with STING1. Interacts with USP20.

Subcellular location. Cytoplasm Nucleus. Cytoplasm.

Disease relevance. Pseudo-TORCH syndrome 2 (PTORCH2) [MIM:617397] An autosomal recessive multisystem disorder characterized by antenatal onset of intracranial hemorrhage, calcification, brain malformations, liver dysfunction, and often thrombocytopenia. Affected individuals tend to have respiratory insufficiency and seizures, and die in infancy. The phenotype resembles the sequelae of intrauterine infection, but there is no evidence of an infectious agent. The disease is caused by variants affecting the gene represented in this entry.

Induction. By type I interferon, predominantly IFN-beta.

Miscellaneous. Produced by alternative initiation at a CTG start codon. An IRES Element in the 5’ region contributes to expression.

Similarity. Belongs to the peptidase C19 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UMW8-1	1	yes
Q9UMW8-2	2, USP18-sf

RefSeq proteins (1): NP_059110* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001394	Peptidase_C19_UCH	Domain
IPR018200	USP_CS	Conserved_site
IPR028889	USP	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050164	Peptidase_C19	Family

Pfam: PF00443

UniProt features (15 total): region of interest 5, sequence variant 2, active site 2, chain 1, domain 1, splice variant 1, mutagenesis site 1, sequence conflict 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
9QY8	X-RAY DIFFRACTION	1.92
9ZFO	ELECTRON MICROSCOPY	3.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UMW8-F1	83.60	0.69

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 (2): 64 (nucleophile); 318 (proton acceptor)

Mutagenesis-validated functional residues (1):

Position	Phenotype
64	abolishes deubiquitinating activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation
R-HSA-5689880	Ub-specific processing proteases
R-HSA-912694	Regulation of IFNA/IFNB signaling
R-HSA-9758274	Regulation of NF-kappa B signaling

MSigDB gene sets: 475 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, FISCHER_G1_S_CELL_CYCLE, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, GOBP_NEGATIVE_REGULATION_OF_INNATE_IMMUNE_RESPONSE, WONG_PROTEASOME_GENE_MODULE

GO Biological Process (9): proteolysis (GO:0006508), response to bacterium (GO:0009617), protein deubiquitination (GO:0016579), regulation of protein stability (GO:0031647), response to stilbenoid (GO:0035634), regulation of inflammatory response (GO:0050727), negative regulation of type I interferon-mediated signaling pathway (GO:0060339), antiviral innate immune response (GO:0140374), response to other organism (GO:0051707)

GO Molecular Function (7): cysteine-type deubiquitinase activity (GO:0004843), ISG15-specific peptidase activity (GO:0019785), molecular adaptor activity (GO:0060090), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Antimicrobial mechanism of IFN-stimulated genes	1
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	1
Toll Like Receptor 3 (TLR3) Cascade	1
Interleukin-1 signaling	1
TRIF (TICAM1)-mediated TLR4 signaling	1
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	1
MyD88 cascade initiated on plasma membrane	1
Deubiquitination	1
Interferon alpha/beta signaling	1
TAK1-dependent IKK and NF-kappa-B activation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cysteine-type peptidase activity	2
binding	2
cellular anatomical structure	2
protein metabolic process	1
response to other organism	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
regulation of biological quality	1
response to chemical	1
inflammatory response	1
regulation of defense response	1
regulation of response to external stimulus	1
negative regulation of cytokine-mediated signaling pathway	1
negative regulation of innate immune response	1
type I interferon-mediated signaling pathway	1
regulation of type I interferon-mediated signaling pathway	1
innate immune response	1
defense response to virus	1
response to external biotic stimulus	1
biological process involved in interspecies interaction between organisms	1
deubiquitinase activity	1
ubiquitin-like protein peptidase activity	1
molecular_function	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1520 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
USP18	IFNAR2	P48551	996
USP18	ISG15	P05161	959
USP18	UBA7	P41226	882
USP18	HERC5	Q9UII4	873
USP18	USP20	Q9Y2K6	836
USP18	UBE2L6	O14933	824
USP18	OAS1	P00973	805
USP18	IFNAR1	P17181	789
USP18	STAT2	P52630	779
USP18	IRF7	Q92985	774
USP18	JAK1	P23458	772
USP18	IFNB1	P01574	760
USP18	RTP4	Q96DX8	736
USP18	MX1	P20591	733
USP18	OASL	Q15646	730

IntAct

38 interactions, top by confidence:

A	B	Type	Score
USP18	ISG15	psi-mi:“MI:0915”(physical association)	0.870
ISG15	USP18	psi-mi:“MI:0915”(physical association)	0.870
USP18	USP41	psi-mi:“MI:0915”(physical association)	0.560
HTT	USP18	psi-mi:“MI:0915”(physical association)	0.560
USP18		psi-mi:“MI:0915”(physical association)	0.400
USP18	SKP2	psi-mi:“MI:0915”(physical association)	0.400
STAT2	USP18	psi-mi:“MI:0915”(physical association)	0.400
USP18	IFNAR2	psi-mi:“MI:0915”(physical association)	0.400
IFNAR2	USP18	psi-mi:“MI:0915”(physical association)	0.400
USP18	FKBP5	psi-mi:“MI:0915”(physical association)	0.400
MLF1	USP18	psi-mi:“MI:0915”(physical association)	0.400
USP18	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
NUDCD3	USP18	psi-mi:“MI:0915”(physical association)	0.400
SGTA	USP18	psi-mi:“MI:0915”(physical association)	0.400
USP18	STIP1	psi-mi:“MI:0915”(physical association)	0.400
FKBPL	USP18	psi-mi:“MI:0915”(physical association)	0.400
CACYBP	USP18	psi-mi:“MI:0915”(physical association)	0.400
USP18	AARSD1	psi-mi:“MI:0915”(physical association)	0.400
USP18	PPP5C	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (124): SKP2 (Affinity Capture-Western), ISG15 (Affinity Capture-Western), USP18 (Two-hybrid), USP18 (Affinity Capture-RNA), USP18 (Affinity Capture-RNA), USP18 (Two-hybrid), USP41 (Affinity Capture-MS), HERC1 (Affinity Capture-MS), USP18 (Two-hybrid), USP18 (Affinity Capture-Western), USP18 (Affinity Capture-Western), USP18 (Affinity Capture-Western), USP18 (Affinity Capture-Western), TMEM14A (Two-hybrid), USP18 (Affinity Capture-Western)

ESM2 similar proteins: A0JM59, A2BGT0, A4QNN3, A5PMR2, A5PN09, A6QNM7, A7Z056, A8HAL1, B1AY15, B1WBD7, D3ZPG5, E1C213, E2RK09, E7F6T8, E9QG68, F1N5V1, F1SRY5, P51944, P52479, P97573, Q0VA64, Q14155, Q15052, Q28CN3, Q2KJ09, Q3KR59, Q3UN04, Q5R5Z6, Q5RE63, Q5REG5, Q5XXR3, Q70CQ3, Q70CQ4, Q70EK9, Q86T82, Q8BW70, Q8C0R0, Q8C2S0, Q8C6M1, Q8K4I3

Diamond homologs: A0A0R4IB93, A0JM59, A5PMR2, A5PN09, A6NNY8, A6QNM7, A7Z056, B1AY13, B1WBD7, D2HBJ8, D6RBM5, E1C213, E7F6T8, E9Q9U0, F6Z5C0, F8VPU6, F8VPZ3, M9PD06, O00507, O22207, O60079, O74442, O94269, O94966, O96612, P0C7I0, P0C8Z3, P0CAQ1, P35125, P39538, P40453, P51784, P53874, P55824, P70398, Q01988, Q09738, Q0V9G5, Q28CN3, Q2HJE4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 21 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
SARS-CoV-2 activates/modulates innate and adaptive immune responses	5	34.3×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	48
Likely benign	13
Benign	9

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1676305	GRCh37/hg19 22q11.1-11.21(chr22:16888899-18644241)x4	Pathogenic
3256725	NM_017414.4(USP18):c.772C>T (p.Arg258Ter)	Pathogenic
417775	USP18, 3-PRIME DEL	Pathogenic
2506027	NM_017414.4(USP18):c.891+1G>T	Likely pathogenic
417774	NM_017414.4(USP18):c.652C>T (p.Gln218Ter)	Likely pathogenic

SpliceAI

1665 predictions. Top by Δscore:

Variant	Effect	Δscore
22:18157754:G:GT	donor_gain	1.0000
22:18158904:G:GT	donor_gain	1.0000
22:18158920:T:G	donor_gain	1.0000
22:18160266:GAG:G	donor_gain	1.0000
22:18161919:G:GT	donor_gain	1.0000
22:18161931:GCCCT:G	donor_gain	1.0000
22:18161936:G:GG	donor_gain	1.0000
22:18167246:T:TA	acceptor_gain	1.0000
22:18167248:T:TA	acceptor_gain	1.0000
22:18167249:G:A	acceptor_gain	1.0000
22:18167253:A:AG	acceptor_gain	1.0000
22:18167254:G:GA	acceptor_gain	1.0000
22:18167254:GT:G	acceptor_gain	1.0000
22:18167884:TTGCA:T	acceptor_loss	1.0000
22:18167887:CAGGT:C	acceptor_loss	1.0000
22:18167888:A:AG	acceptor_gain	1.0000
22:18167888:AGGT:A	acceptor_gain	1.0000
22:18167888:AGGTG:A	acceptor_gain	1.0000
22:18167889:G:GT	acceptor_gain	1.0000
22:18167889:GGT:G	acceptor_gain	1.0000
22:18167889:GGTG:G	acceptor_gain	1.0000
22:18167889:GGTGG:G	acceptor_gain	1.0000
22:18167960:A:T	donor_gain	1.0000
22:18169832:T:TA	acceptor_gain	1.0000
22:18173148:A:AG	acceptor_gain	1.0000
22:18173148:AGTCT:A	acceptor_gain	1.0000
22:18173149:G:GA	acceptor_gain	1.0000
22:18173149:GT:G	acceptor_gain	1.0000
22:18173149:GTCT:G	acceptor_gain	1.0000
22:18173149:GTCTG:G	acceptor_gain	1.0000

AlphaMissense

2479 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:18170804:T:C	F259L	0.979
22:18170806:C:A	F259L	0.979
22:18170806:C:G	F259L	0.979
22:18173249:T:A	W331R	0.970
22:18173249:T:C	W331R	0.970
22:18160184:T:C	L57S	0.966
22:18173266:C:A	D336E	0.961
22:18173266:C:G	D336E	0.961
22:18170852:T:C	F275L	0.957
22:18170854:C:A	F275L	0.957
22:18170854:C:G	F275L	0.957
22:18173265:A:C	D336A	0.956
22:18173265:A:T	D336V	0.956
22:18160215:C:A	N67K	0.953
22:18160215:C:G	N67K	0.953
22:18173174:G:C	A306P	0.953
22:18173175:C:A	A306D	0.942
22:18173178:T:A	V307E	0.942
22:18176783:C:A	A362E	0.941
22:18160191:C:A	N59K	0.940
22:18160191:C:G	N59K	0.940
22:18176797:T:G	Y367D	0.939
22:18161831:T:A	V99D	0.938
22:18170853:T:C	F275S	0.930
22:18173264:G:C	D336H	0.928
22:18173171:T:C	F305L	0.926
22:18173173:T:A	F305L	0.926
22:18173173:T:G	F305L	0.926
22:18176789:T:C	L364P	0.921
22:18160207:T:C	C65R	0.920

dbSNP variants (sampled 300 via entrez): RS1000236794 (22:18172201 C>A), RS1000453986 (22:18162255 A>G), RS1000586643 (22:18168166 G>A,T), RS1000612879 (22:18167750 C>T), RS1000655590 (22:18151349 C>T), RS1001116792 (22:18157502 A>G), RS1001250944 (22:18152803 T>G), RS1001421578 (22:18156979 A>G,T), RS1001528515 (22:18157205 C>T), RS1001534388 (22:18163327 T>C), RS1001588491 (22:18169432 C>G), RS1001619828 (22:18169112 G>A), RS1001787857 (22:18155734 G>A,C), RS1001860526 (22:18163663 A>AT), RS1001996239 (22:18148908 G>A,T)

Disease associations

OMIM: gene MIM:607057 | disease phenotypes: MIM:115470, MIM:617397

GenCC curated gene-disease

Disease	Classification	Inheritance
pseudo-TORCH syndrome 2	Definitive	Autosomal recessive

Mondo (2): cat-eye syndrome (MONDO:0007276), pseudo-TORCH syndrome 2 (MONDO:0018828)

Orphanet (2): Cat-eye syndrome (Orphanet:195), Pseudo-TORCH syndrome type 2 (Orphanet:481665)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000883	Thin ribs
HP:0000967	Petechiae
HP:0001250	Seizure
HP:0001254	Lethargy
HP:0001290	Generalized hypotonia
HP:0001321	Cerebellar hypoplasia
HP:0001342	Cerebral hemorrhage
HP:0001541	Ascites
HP:0001643	Patent ductus arteriosus
HP:0001662	Bradycardia
HP:0001684	Secundum atrial septal defect
HP:0001873	Thrombocytopenia
HP:0002093	Respiratory insufficiency
HP:0002119	Ventriculomegaly
HP:0002126	Polymicrogyria
HP:0002202	Pleural effusion
HP:0002240	Hepatomegaly
HP:0002282	Gray matter heterotopia
HP:0002514	Cerebral calcification
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003128	Lactic acidosis
HP:0003623	Neonatal onset
HP:0005932	Abnormal renal corticomedullary differentiation
HP:0006956	Lateral ventricle dilatation
HP:0011461	Fetal onset
HP:0025116	Fetal distress
HP:0033677	Acute respiratory distress syndrome

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST011956_119	Systemic lupus erythematosus	6.000000e-11

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535918	Schmid-Fraccaro syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3407317 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	decreases expression, increases expression, affects response to substance	4
Estradiol	affects cotreatment, increases expression, decreases expression	3
Lipopolysaccharides	increases secretion, increases expression, decreases activity, decreases reaction, increases phosphorylation	2
Toluene	increases expression	2
Valproic Acid	affects cotreatment, increases expression	2
ethylbenzene	increases expression	1
methylmercuric chloride	increases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases abundance, increases expression, affects cotreatment	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	decreases expression	1
2-xylene	increases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
monophosphoryl lipid A	decreases activity, decreases reaction, increases expression, increases phosphorylation, increases secretion	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
tofacitinib	decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
incobotulinumtoxinA	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3412536	Binding	Inhibition of recombinant human USP18 (16 to 372 aa) expressed in Sf9 cells using ISG15-AMC as substrate preincubated for 30 mins before substrate addition measured after 60 mins by fluorescence assay	Synthesis, characterization, and optimization for in vivo delivery of a nonselective isopeptidase inhibitor as new antineoplastic agent. — J Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1IF	Abcam A-549 USP18 KO 1	Cancer cell line	Male
CVCL_B2KJ	Abcam HeLa USP18 KO	Cancer cell line	Female
CVCL_B2QZ	Abcam A-549 USP18 KO 2	Cancer cell line	Male
CVCL_TW66	HAP1 USP18 (-) 1	Cancer cell line	Male
CVCL_TW67	HAP1 USP18 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02067806	Not specified	COMPLETED	Observational Study on 2-chloroprocaine Hydrochloride 1%
NCT04465136	Not specified	TERMINATED	CES in the Elderly With Generalized Anxiety Disorders