Q6R6M4 (U17L2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Ubiquitin carboxyl-terminal hydrolase 17
Short name=USP17
EC=3.4.19.12

Alternative name(s):
Deubiquitinating enzyme 17-like protein 2
Deubiquitinating protein 3
Short name=DUB-3
Ubiquitin carboxyl-terminal hydrolase 17-like protein 2
Ubiquitin thioesterase 17-like protein 2
Ubiquitin-specific-processing protease 17-like protein 2

Gene names

Name:	USP17L2
Synonyms:	DUB3, USP17, USP17H, USP17I, USP17J, USP17K, USP17L, USP17M

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	530 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Deubiquitinating enzyme that removes conjugated ubiquitin from specific proteins to regulate different cellular processes. Regulates cell proliferation by deubiquitinating and inhibiting RCE1 thereby controlling the small GTPases NRAS and HRAS localization and activation. In parallel, mediates deubiquitination of CDC25A, preventing CDC25A degradation by the proteasome during the G1/S and G2/M phases promoting cell-cycle progression. Also regulates cell proliferation and apoptosis through deubiquitination of SUDS3 a regulator of histone deacetylation. Through activation of the Rho family GTPases RAC1A, CDC42 and RHOA, regulates cell migration. Through the cleavage of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains of the cytoplasmic innate immune receptors DDX58 and IFIH1 stimulates the cellular response to viral infection. Ref.1 Ref.4 Ref.5 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12
Catalytic activity	Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal). Ref.1 Ref.8 Ref.10
Subunit structure	Interacts with SUDS3; the interaction is direct. Ref.11
Subcellular location	Nucleus. Endoplasmic reticulum Ref.5 Ref.11.
Tissue specificity	Broadly expressed. Ref.1
Induction	Up-regulated by IL4/interleukin-4, IL6/interleukin-6 and chemokines including CXCL8 and CXCL12 (at protein level). Up-regulated during the G1/S transition of the cell cycle. Ref.1 Ref.7 Ref.12
Miscellaneous	Overexpressed in a subset of human breast cancers, overexpression leading to an abnormally high level of CDC25A, which arrests cells through replication stress or premature mitosis, the latter occurring when CDK1 is activated inappropriately (Ref.10).
Sequence similarities	Belongs to the peptidase C19 family. USP17 subfamily.
Caution	The RS447 megasatellite DNA is a highly polymorphic conserved tandem repetitive sequence which contains a copy of the USP17 gene. It is present with an interindividual variation in copy number, ranging from 20 to 103, and can be found in the genome both on chromosome 4 and chromosome 8. USP17 is also frequently named DUB3 in the literature. The high similarity between the UPS17-like genes makes impossible to clearly assign data to one of the genes of the family. Oligonucleotides designed in RNAi experiments are for instance not specific of a given UPS17-like gene.

Ontologies

Keywords
Biological process	Apoptosis Cell cycle Ubl conjugation pathway
Cellular component	Endoplasmic reticulum Nucleus
Coding sequence diversity	Polymorphism
Molecular function	Hydrolase Protease Thiol protease
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	CAAX-box protein processing Inferred from mutant phenotype Ref.5. Source: UniProtKB apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW mitotic cell cycle checkpoint Inferred from mutant phenotype Ref.10. Source: UniProtKB negative regulation of Ras GTPase activity Inferred from direct assay Ref.5. Source: UniProtKB negative regulation of histone deacetylation Inferred from mutant phenotype Ref.11. Source: UniProtKB negative regulation of protein processing Inferred from mutant phenotype Ref.5. Source: UniProtKB negative regulation of protein targeting to membrane Inferred from mutant phenotype Ref.5. Source: UniProtKB positive regulation of MDA-5 signaling pathway Inferred from mutant phenotype Ref.8. Source: UniProtKB positive regulation of RIG-I signaling pathway Inferred from mutant phenotype Ref.8. Source: UniProtKB positive regulation of Rho GTPase activity Inferred from mutant phenotype Ref.12. Source: UniProtKB protein K48-linked deubiquitination Inferred from mutant phenotype Ref.5Ref.8. Source: UniProtKB protein K63-linked deubiquitination Inferred from direct assay Ref.11. Source: UniProtKB regulation of apoptotic process Inferred from mutant phenotype Ref.11. Source: UniProtKB regulation of cell migration Inferred from mutant phenotype Ref.12. Source: UniProtKB regulation of cell proliferation Inferred from mutant phenotype Ref.5. Source: UniProtKB regulation of defense response to virus by host Inferred from mutant phenotype Ref.8. Source: UniProtKB regulation of ruffle assembly Inferred from mutant phenotype Ref.12. Source: UniProtKB ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: InterPro
Cellular_component	endoplasmic reticulum membrane Inferred from direct assay Ref.5. Source: UniProtKB nucleus Inferred from direct assay Ref.11. Source: UniProtKB
Molecular_function	ubiquitin thiolesterase activity Inferred from mutant phenotype Ref.10. Source: UniProtKB ubiquitin-specific protease activity Inferred from direct assay Ref.10Ref.11. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 530	530	Ubiquitin carboxyl-terminal hydrolase 17		PRO_0000331644
Regions
	Region	399 – 530	132	Mediates interaction with SUDS3
Sites
	Active site	89	1	Nucleophile
	Active site	334	1	Proton acceptor By similarity
Natural variations
	Natural variant	438	1	K → R. Corresponds to variant rs12543578 [ dbSNP | Ensembl ].		VAR_059750
Experimental info
	Mutagenesis	89	1	C → S: Abolishes both enzymatic activity and effects on cell proliferation. Ref.1
	Sequence conflict	66	1	K → E in AAR91701. Ref.1
	Sequence conflict	214	1	S → P in AAR91701. Ref.1
	Sequence conflict	332	1	D → N in AAR91701. Ref.1
	Sequence conflict	353	1	K → E in AAR91701. Ref.1
	Sequence conflict	357	1	C → S in AAR91701. Ref.1
	Sequence conflict	423	1	R → H in AAR91701. Ref.1
	Sequence conflict	440	1	P → L in AAR91701. Ref.1
	Sequence conflict	462	1	N → D in AAR91701. Ref.1
	Sequence conflict	494	1	R → P in AAR91701. Ref.1
	Sequence conflict	496	1	D → H in AAR91701. Ref.1
	Sequence conflict	500	1	V → M in AAR91701. Ref.1
	Sequence conflict	509	1	Q → R in AAR91701. Ref.1
	Sequence conflict	512	1	T → A in AAR91701. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q6R6M4 [UniParc]. Last modified April 29, 2008. Version 2. Checksum: B117BB171376B0E4	FASTA	530	59,619
	10 20 30 40 50 60 MEDDSLYLGG EWQFNHFSKL TSSRPDAAFA EIQRTSLPEK SPLSSEARVD LCDDLAPVAR 70 80 90 100 110 120 QLAPRKKLPL SSRRPAAVGA GLQNMGNTCY ENASLQCLTY TPPLANYMLS REHSQTCQRP 130 140 150 160 170 180 KCCMLCTMQA HITWALHSPG HVIQPSQALA AGFHRGKQED AHEFLMFTVD AMKKACLPGH 190 200 210 220 230 240 KQVDHHSKDT TLIHQIFGGC WRSQIKCLHC HGISDTFDPY LDIALDIQAA QSVKQALEQL 250 260 270 280 290 300 VKPEELNGEN AYHCGLCLQR APASKTLTLH TSAKVLILVL KRFSDVTGNK LAKNVQYPEC 310 320 330 340 350 360 LDMQPYMSQQ NTGPLVYVLY AVLVHAGWSC HDGHYFSYVK AQEGQWYKMD DAKVTACSIT 370 380 390 400 410 420 SVLSQQAYVL FYIQKSEWER HSESVSRGRE PRALGAEDTD RRATQGELKR DHPCLQAPEL 430 440 450 460 470 480 DERLVERATQ ESTLDHWKFP QEQNKTKPEF NVRKVEGTLP PNVLVIHQSK YKCGMKNHHP 490 500 510 520 530 EQQSSLLNLS STTRTDQESV NTGTLASLQG RTRRSKGKNK HSKRALLVCQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"DUB-3, a cytokine-inducible deubiquitinating enzyme that blocks proliferation." Burrows J.F., McGrattan M.J., Rascle A., Humbert M., Baek K.-H., Johnston J.A. J. Biol. Chem. 279:13993-14000(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, INDUCTION BY CYTOKINES, TISSUE SPECIFICITY, MUTAGENESIS OF CYS-89.
[2]	"DNA sequence and analysis of human chromosome 8." Nusbaum C., Mikkelsen T.S., Zody M.C., Asakawa S., Taudien S., Garber M., Kodira C.D., Schueler M.G., Shimizu A., Whittaker C.A., Chang J.L., Cuomo C.A., Dewar K., FitzGerald M.G., Yang X., Allen N.R., Anderson S., Asakawa T. , Blechschmidt K., Bloom T., Borowsky M.L., Butler J., Cook A., Corum B., DeArellano K., DeCaprio D., Dooley K.T., Dorris L. III, Engels R., Gloeckner G., Hafez N., Hagopian D.S., Hall J.L., Ishikawa S.K., Jaffe D.B., Kamat A., Kudoh J., Lehmann R., Lokitsang T., Macdonald P., Major J.E., Matthews C.D., Mauceli E., Menzel U., Mihalev A.H., Minoshima S., Murayama Y., Naylor J.W., Nicol R., Nguyen C., O'Leary S.B., O'Neill K., Parker S.C.J., Polley A., Raymond C.K., Reichwald K., Rodriguez J., Sasaki T., Schilhabel M., Siddiqui R., Smith C.L., Sneddon T.P., Talamas J.A., Tenzin P., Topham K., Venkataraman V., Wen G., Yamazaki S., Young S.K., Zeng Q., Zimmer A.R., Rosenthal A., Birren B.W., Platzer M., Shimizu N., Lander E.S. Nature 439:331-335(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"The DUB/USP17 deubiquitinating enzymes, a multigene family within a tandemly repeated sequence." Burrows J.F., McGrattan M.J., Johnston J.A. Genomics 85:524-529(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NOMENCLATURE.
[4]	"Hyaluronan- and RNA-binding deubiquitinating enzymes of USP17 family members associated with cell viability." Shin J.-M., Yoo K.-J., Kim M.-S., Kim D., Baek K.-H. BMC Genomics 7:292-292(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NOMENCLATURE, FUNCTION IN APOPTOSIS.
[5]	"USP17 regulates Ras activation and cell proliferation by blocking RCE1 activity." Burrows J.F., Kelvin A.A., McFarlane C., Burden R.E., McGrattan M.J., De la Vega M., Govender U., Quinn D.J., Dib K., Gadina M., Scott C.J., Johnston J.A. J. Biol. Chem. 284:9587-9595(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN CELL PROLIFERATION, SUBCELLULAR LOCATION.
[6]	"The DUB/USP17 deubiquitinating enzymes: a gene family within a tandemly repeated sequence, is also embedded within the copy number variable beta-defensin cluster." Burrows J.F., Scott C.J., Johnston J.A. BMC Genomics 11:250-250(2010) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION.
[7]	"The deubiquitinating enzyme USP17 is highly expressed in tumor biopsies, is cell cycle regulated, and is required for G1-S progression." McFarlane C., Kelvin A.A., de la Vega M., Govender U., Scott C.J., Burrows J.F., Johnston J.A. Cancer Res. 70:3329-3339(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INDUCTION.
[8]	"The ubiquitin-specific protease 17 is involved in virus-triggered type I IFN signaling." Chen R., Zhang L., Zhong B., Tan B., Liu Y., Shu H.B. Cell Res. 20:802-811(2010) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, FUNCTION IN CELLULAR ANTIVIRAL RESPONSE.
[9]	"The deubiquitinating enzyme USP17 blocks N-Ras membrane trafficking and activation but leaves K-Ras unaffected." de la Vega M., Burrows J.F., McFarlane C., Govender U., Scott C.J., Johnston J.A. J. Biol. Chem. 285:12028-12036(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[10]	"Ubiquitin hydrolase Dub3 promotes oncogenic transformation by stabilizing Cdc25A." Pereg Y., Liu B.Y., O'Rourke K.M., Sagolla M., Dey A., Komuves L., French D.M., Dixit V.M. Nat. Cell Biol. 12:400-406(2010) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, FUNCTION IN CELL PROLIFERATION.
[11]	"Lys-63-specific deubiquitination of SDS3 by USP17 regulates HDAC activity." Ramakrishna S., Suresh B., Lee E.J., Lee H.J., Ahn W.S., Baek K.H. J. Biol. Chem. 286:10505-10514(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH SUDS3, SUBCELLULAR LOCATION.
[12]	"The deubiquitinating enzyme USP17 is essential for GTPase subcellular localization and cell motility." de la Vega M., Kelvin A.A., Dunican D.J., McFarlane C., Burrows J.F., Jaworski J., Stevenson N.J., Dib K., Rappoport J.Z., Scott C.J., Long A., Johnston J.A. Nat. Commun. 2:259-259(2011) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN CELL MIGRATION, INDUCTION BY CHEMOKINE.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AY509884 mRNA. Translation: AAR91701.1. AC130366 Genomic DNA. No translation available.
IPI	IPI00883911.
RefSeq	NP_958804.2. NM_201402.2.
UniGene	Hs.531448.
3D structure databases
HSSP	HSSP built from PDB template 2AYO based on UniProtKB P54578.
ProteinModelPortal	Q6R6M4.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q6R6M4. 4 interactions.
STRING	9606.ENSP00000333329.
Polymorphism databases
DMDM	187663988.
Proteomic databases
PaxDb	Q6R6M4.
PRIDE	Q6R6M4.
Protocols and materials databases
DNASU	377630.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000333796; ENSP00000333329; ENSG00000223443.
GeneID	377630.
KEGG	hsa:377630.
UCSC	uc003wvc.1. human.
Organism-specific databases
CTD	377630.
GeneCards	GC08M011994.
H-InvDB	HIX0034323.
HGNC	HGNC:34434. USP17L2.
HPA	HPA045642.
MIM	610186. gene.
neXtProt	NX_Q6R6M4.
PharmGKB	PA165586023.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG5533.
HOGENOM	HOG000144638.
HOVERGEN	HBG007129.
InParanoid	Q6R6M4.
KO	K11845.
OrthoDB	EOG42V8G0.
PhylomeDB	Q6R6M4.
Gene expression databases
Genevestigator	Q6R6M4.
Family and domain databases
InterPro	IPR006861. HABP4_PAIRBP1-bd. IPR018200. Pept_C19ubi-hydrolase_C_CS. IPR001394. Peptidase_C19. [Graphical view]
Pfam	PF04774. HABP4_PAI-RBP1. 1 hit. PF00443. UCH. 1 hit. [Graphical view]
PROSITE	PS00972. UCH_2_1. False negative. PS00973. UCH_2_2. 1 hit. PS50235. UCH_2_3. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	377630.
NextBio	100679.
SOURCE	Search...

Entry information

Entry name

U17L2_HUMAN

Accession

Primary (citable) accession number: Q6R6M4

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 29, 2008
Last sequence update:	April 29, 2008
Last modified:	May 1, 2013
This is version 67 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.