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]
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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Gray D (2012). "Chapter 462". In Rawlings & Salvesen (ed.). Handbook of Proteolytic Enzymes (3rd ed.). Elsevier. ISBN9780123822192.
^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. PMID8336951.
^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. PMID9602026.
^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. PMID12838346. S2CID2856065.
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. PMID9827704.
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. PMID7784062.
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. PMID8125298.
Gupta K, Chevrette M, Gray DA (1994). "The Unp proto-oncogene encodes a nuclear protein". Oncogene. 9 (6): 1729–31. PMID8183569.
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. PMID9373149.
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. PMID11461834.
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. PMID16316627.
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. PMID16472766.
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