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FLASH GENE

Symbol

USP18

contributors: mct/npt - updated : 31-01-2016

HGNC name	ubiquitin specific peptidase 18
HGNC id	12616

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol blood / hematopoietic thymus         Digestive liver       highly Respiratory respiratory tract larynx     highly Urinary bladder       highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Lymphoid

cell lineage	hematopoiesis
cell lines	differentiated human melanoma cells
fluid/secretion

at STAGE

physiological period

fetal

Text

spleen

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	short consensus sequences surrunding Cys (Cys box) and histidine (His box)
	two other conserved domains commun to deubiquitin enzymes c
	a critical hydrophobic patch in USP18 interacts with a hydrophobic region unique to ISG15, thus providing evidence that USP18's ISG15 specificity is mediated by a small interaction interface

HOMOLOGY

interspecies

ortholog to murine Ubp43

intraspecies

paralog to ubiquitin specific protein proteases UBR

Homologene

FAMILY	deubiquitinating protease family
	peptidase C19 family

CATEGORY

enzyme

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus

basic FUNCTION	deubiquitin enzyme, hydrolyzing isopeptide bonds between UB and folded protein domains such as additional UB moieties or target proteins
	regulating BCR-ABL leukemogenesis via the type 1 interferon receptor signaling
	G1P2 deconjugating protease having a role in innate immunity against viral infection
	type I IFN-induced protein that deconjugates the ubiquitin-like modifier ISG15 from target proteins, was found to limit apoptotic susceptibility to IFNA or bortezomib
	may significantly limit operation of the extrinsic apoptotic pathway triggered by type I IFN and drugs
	IFN-inducible member of the ubiquitin-specific protease family
	novel role in modulating conventional CD11b(+) dendritic cells development via its inhibitory effect on type I IFN signaling
	plays a role in the negative regulation of interferon-alpha/beta signaling
	removes ISG15 from conjugated proteins
	key regulator of IFN signaling in beta cells, underlining the importance of this pathway in beta cell inflammation and death
	roles of USP18 and USP20 in mediating virus-triggered signaling

CELLULAR PROCESS	protein, ubiquitin dependent proteolysis
	cell organization/biogenesis

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	interacting with G1P2 (to maintain a critical cellular balance of G1P2-conjugated proteins in both healthy and stressed organism)
	its overexpression elevated EGFR levels in a manner requiring the catalytic cysteine of USP18
	potent regulator of EGFR protein expression
	direct relationship was found between USP18 and CCND1 (but not cyclin E) expression
	covalent linkage of ISG15 interferes with viral infection and USP18 is the major protease which specifically removes ISG15 from target proteins
	USP18 is a transcriptional target of WT1, suggesting that increased expression of USP18 following WT1 loss contributes to Wilms tumorigenesis
	IRS4 functioned as a novel USP18-binding protein

cell & other

REGULATION

activated by

upregulated in normal tumor cells when treated with IFN beta, via the JAK/STAT pathway

induced by

INF1, genotoxic stress and viral infection

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral         increases the resistance to oncogenic transformation by BCR-ABL tumoral     --over   increased in the malignant versus normal lung constitutional       loss of function induces inflammation by increasing the STAT signaling and exacerbates IFN-induced beta cell apoptosis by the mitochondrial pathway of cell death constitutional     --low   promotes up-regulation of MIR7-1, which in turn inhibits EGFR expression and the tumorigenic activity of cancer cells

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer hemopathy   novel candidate drug target for acute promyelocytic leukemia treatment cancer     antineoplastic target cancer     pharmacological inhibition of UBP43 may be of benefit in cancers and others diseases in which interferon is currently prescribed immunology infectious   therapeutic potential of modulating USP18 levels in treating viral infection, especially for viruses sensitive to IFN signaling

ANIMAL & CELL MODELS

	deletion of murine Usp18 causes an increase in free and conjugated Isg15 at the feto-maternal interface and results in fetal death
	bone marrow cells in Ubp43-deficient mice exhibited hypersensitivity to interferon-alpha/beta-mediated apoptosis