USP4

Ubiquitin specific protease 4 (USP4) is an enzyme that cleaves ubiquitin from a number of protein substrates.[5] Prior to the standardization of nomenclature USP4 was known as UNP, and was one of the first deubiquitinating enzymes to be identified in mammals.[6] In the mouse and human the USP4 protein is encoded by a gene containing 22 exons.[7][8][9]

USP4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2Y6E, 5CTR
Identifiers
Aliases	USP4, UNP, Unph, ubiquitin specific peptidase 4
External IDs	OMIM: 603486 MGI: 98905 HomoloGene: 20716 GeneCards: USP4
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3p21.31 Start 49,277,144 bp[1] End 49,340,712 bp[1]
Gene location (Mouse) Chr. Chromosome 9 (mouse)[2] Band 9 F2|9 59.25 cM Start 108,347,853 bp[2] End 108,392,545 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • peptidase activity • adenosine receptor binding • hydrolase activity • thiol-dependent ubiquitin-specific protease activity • metal ion binding • cysteine-type peptidase activity • identical protein binding • GO:0001948 protein binding Cellular component • cell nucleus • lysosome • cell membrane • cytoplasm • cytosol Biological process • ubiquitin-dependent protein catabolic process • spliceosomal tri-snRNP complex assembly • regulation of protein stability • proteolysis • negative regulation of protein ubiquitination • protein localization to cell surface • protein deubiquitination Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	7375	22258
Ensembl	ENSG00000114316	ENSMUSG00000032612
UniProt	Q13107	P35123
RefSeq (mRNA)	NM_199443 NM_001251877 NM_003363	NM_011678 NM_001311157
RefSeq (protein)	NP_001238806 NP_003354 NP_955475	NP_001298086 NP_035808
Location (UCSC)	Chr 3: 49.28 – 49.34 Mb	Chr 9: 108.35 – 108.39 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

This protein is a member of cysteine peptidase family C19. As a deubiquitinating enzyme it is unusual in having the capacity to cleave ubiquitin-proline bonds.[10] This property may reflect structural flexibility in the active site of the enzyme, and may explain its ability to cleave ubiquitin chains of various linkages. USP4 has substrates of important function in a number of cell signalling pathways, including the NF-κB, TGF-β, Wnt/β-catenin, p53, and spliceosome pathways. Other substrates include the adenosine A2A receptor and the Ro52 (TRIM21) protein.

USP4 is a nucleocytoplasmic shuttling protein that bears a functional nuclear localization signal (NLS) ⁷⁶⁶QPQKKKK⁷⁷² and a nuclear export signal (NES) ¹³³VEVYLLELKL¹⁴².[11] Those signals initiate the translocation of USP4 to the nucleus from the cytoplasm and vice versa, respectively. The proportion of cytoplasmic to nuclear USP4 pool varies depending on the cell type, the phase of cell cycle and the level of protein expression.[11]

Interactions

USP4 has been shown to interact with the tumor suppressor pRb protein and the pocket-related proteins p107 and p130.[12]

References

1. GRCh38: Ensembl release 89: ENSG00000114316 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000032612 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Gray D (2012). "Chapter 462". In Rawlings & Salvesen (ed.). Handbook of Proteolytic Enzymes (3rd ed.). Elsevier. ISBN 9780123822192.
6. Gupta K, Copeland NG, Gilbert DJ, Jenkins NA, Gray DA (August 1993). "Unp, a mouse gene related to the tre oncogene". Oncogene. 8 (8): 2307–10. PMID 8336951.
7. Di Fruscio M, Gilchrist CA, Baker RT, Gray DA (May 1998). "Genomic structure of Unp, a murine gene encoding a ubiquitin-specific protease". Biochim. Biophys. Acta. 1398 (1): 9–17. doi:10.1016/s0167-4781(98)00035-9. PMID 9602026.
8. Puente XS, Sanchez LM, Overall CM, Lopez-Otin C (July 2003). "Human and mouse proteases: a comparative genomic approach". Nat Rev Genet. 4 (7): 544–558. doi:10.1038/nrg1111. PMID 12838346. S2CID 2856065.
9. "Entrez Gene: USP4 ubiquitin specific peptidase 4 (proto-oncogene)".
10. Gilchrist CA, Gray DA, Baker RT (December 1997). "A ubiquitin-specific protease that efficiently cleaves the ubiquitin-proline bond". J. Biol. Chem. 272 (51): 32280–5. doi:10.1074/jbc.272.51.32280. PMID 9405433.
11. Soboleva, Tatiana A.; Jans, David A.; Johnson-Saliba, Melanie; Baker, Rohan T. (2004-10-18). "Nuclear-Cytoplasmic Shuttling of the Oncogenic Mouse UNP/USP4 Deubiquitylating Enzyme". Journal of Biological Chemistry. 280 (1): 745–752. doi:10.1074/jbc.m401394200. ISSN 0021-9258. PMID 15494318.
12. Blanchette, Paola; Gilchrist, Catherine A; Baker, Rohan T; Gray, Douglas A (September 2001). "Association of UNP, a ubiquitin-specific protease, with the pocket proteins pRb, p107 and p130". Oncogene. 20 (39): 5533–5537. doi:10.1038/sj.onc.1204823. ISSN 0950-9232. PMID 11571651.

Further reading

• D'Andrea A, Pellman D (1999). "Deubiquitinating enzymes: a new class of biological regulators". Crit. Rev. Biochem. Mol. Biol. 33 (5): 337–352. doi:10.1080/10409239891204251. PMID 9827704.
• Gray DA, Inazawa J, Gupta K, et al. (1995). "Elevated expression of Unph, a proto-oncogene at 3p21.3, in human lung tumors". Oncogene. 10 (11): 2179–83. PMID 7784062.
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
• Gupta K, Chevrette M, Gray DA (1994). "The Unp proto-oncogene encodes a nuclear protein". Oncogene. 9 (6): 1729–31. PMID 8183569.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
• Di Donato F, Chan EK, Askanase AD, et al. (2001). "Interaction between 52 kDa SSA/Ro and deubiquitinating enzyme UnpEL: a clue to function". Int. J. Biochem. Cell Biol. 33 (9): 924–934. doi:10.1016/S1357-2725(01)00055-3. PMID 11461834.
• Blanchette P, Gilchrist CA, Baker RT, Gray DA (2001). "Association of UNP, a ubiquitin-specific protease, with the pocket proteins pRb, p107 and p130". Oncogene. 20 (39): 5533–5537. doi:10.1038/sj.onc.1204823. PMID 11571651.
• DeSalle LM, Latres E, Lin D, et al. (2001). "The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein". Oncogene. 20 (39): 5538–5542. doi:10.1038/sj.onc.1204824. PMID 11571652.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–16903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–2127. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Wada K, Tanji K, Kamitani T (2006). "Oncogenic protein UnpEL/Usp4 deubiquitinates Ro52 by its isopeptidase activity". Biochem. Biophys. Res. Commun. 339 (3): 731–736. doi:10.1016/j.bbrc.2005.11.076. PMID 16316627.
• Wada K, Kamitani T (2006). "UnpEL/Usp4 is ubiquitinated by Ro52 and deubiquitinated by itself". Biochem. Biophys. Res. Commun. 342 (1): 253–258. doi:10.1016/j.bbrc.2006.01.144. PMID 16472766.

External links

• Overview of all the structural information available in the PDB for UniProt: Q13107 (Ubiquitin carboxyl-terminal hydrolase 4) at the PDBe-KB.