Nuclear-cytoplasmic shuttling of the oncogenic mouse UNP/USP4 deubiquitylating enzyme
- PMID: 15494318
- DOI: 10.1074/jbc.M401394200
Nuclear-cytoplasmic shuttling of the oncogenic mouse UNP/USP4 deubiquitylating enzyme
Abstract
The oncogenic deubiquitylating enzyme (DUB) Unp/Usp4, which binds to the retinoblastoma family of tumor suppressor proteins, was originally described as a nuclear protein. However, more recent studies have shown it to be cytoplasmic. In addition, analysis of its subcellular localization has been complicated by the existence of the paralog Usp15. In this study, we resolved this controversy by investigating the localization of exogenously expressed Usp4 (using red fluorescent protein-Usp4) and of endogenous Usp4 (using highly specific antibodies that can distinguish Usp4 from Usp15). We found that by inhibiting nuclear export with leptomycin B, both exogenous and endogenous Usp4 accumulate in the nucleus. Further, using a Rev-green fluorescent protein-based export assay, we confirmed the existence of a nuclear export signal ((133)VEVYLLELKL(142)) in Usp4. In addition, a functional nuclear import signal ((766)QPQKKKK(772)) was also identified, which was specifically recognized by importin alpha/beta. Finally, we show that the equilibrium of Usp4 subcellular localization varies between different cell types. Usp4 is thus the first DUB reported to have nucleocytoplasmic shuttling properties. The implications of this shuttling for its function as a DUB are discussed.
Similar articles
-
Isolation and characterization of the mouse ubiquitin-specific protease Usp15.Mamm Genome. 2003 Jan;14(1):31-46. doi: 10.1007/s00335-002-3035-0. Mamm Genome. 2003. PMID: 12532266
-
Identification, functional characterization, and chromosomal localization of USP15, a novel human ubiquitin-specific protease related to the UNP oncoprotein, and a systematic nomenclature for human ubiquitin-specific proteases.Genomics. 1999 Aug 1;59(3):264-74. doi: 10.1006/geno.1999.5879. Genomics. 1999. PMID: 10444327
-
USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type I receptor.Nat Cell Biol. 2012 Jun 17;14(7):717-26. doi: 10.1038/ncb2522. Nat Cell Biol. 2012. PMID: 22706160
-
Nucleocytoplasmic shuttling of phospholipase C-delta1: a link to Ca2+.J Cell Biochem. 2006 Feb 1;97(2):233-43. doi: 10.1002/jcb.20677. J Cell Biochem. 2006. PMID: 16240320 Review.
-
Spotlight on USP4: Structure, Function, and Regulation.Front Cell Dev Biol. 2021 Feb 18;9:595159. doi: 10.3389/fcell.2021.595159. eCollection 2021. Front Cell Dev Biol. 2021. PMID: 33681193 Free PMC article. Review.
Cited by
-
Function of ubiquitin (Ub) specific protease 15 (USP15) in HIV-1 replication and viral protein degradation.Virus Res. 2016 Sep 2;223:161-9. doi: 10.1016/j.virusres.2016.07.009. Epub 2016 Jul 25. Virus Res. 2016. PMID: 27460547 Free PMC article.
-
Ubiquitin-proteasome system as a target for anticancer treatment-an update.Arch Pharm Res. 2023 Jul;46(7):573-597. doi: 10.1007/s12272-023-01455-0. Epub 2023 Aug 5. Arch Pharm Res. 2023. PMID: 37541992 Review.
-
The DUSP-Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange.Nat Commun. 2014 Nov 18;5:5399. doi: 10.1038/ncomms6399. Nat Commun. 2014. PMID: 25404403 Free PMC article.
-
The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway.J Cell Mol Med. 2009 Aug;13(8B):1886-95. doi: 10.1111/j.1582-4934.2009.00682.x. J Cell Mol Med. 2009. PMID: 20141612 Free PMC article.
-
Ubiquitin specific protease 4 positively regulates the WNT/β-catenin signaling in colorectal cancer.Mol Oncol. 2015 Nov;9(9):1834-51. doi: 10.1016/j.molonc.2015.06.006. Epub 2015 Jul 3. Mol Oncol. 2015. PMID: 26189775 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
