Spotlight on USP4: Structure, Function, and Regulation

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2021 Mar 8

PMID 33681193

Citations 22

Authors

Binbin Hu

Dingyue Zhang

Kejia Zhao

Yang Wang

Lijiao Pei

Qianmei Fu

Xuelei Ma

Affiliations

Soon will be listed here.

Abstract

The deubiquitinating enzyme (DUB)-mediated cleavage of ubiquitin plays a critical role in balancing protein synthesis and degradation. Ubiquitin-specific protease 4 (USP4), a member of the largest subfamily of cysteine protease DUBs, removes monoubiquitinated and polyubiquitinated chains from its target proteins. USP4 contains a DUSP (domain in USP)-UBL (ubiquitin-like) domain and a UBL-insert catalytic domain, sharing a common domain organization with its paralogs USP11 and USP15. USP4 plays a critical role in multiple cellular and biological processes and is tightly regulated under normal physiological conditions. When its expression or activity is aberrant, USP4 is implicated in the progression of a wide range of pathologies, especially cancers. In this review, we comprehensively summarize the current knowledge of USP4 structure, biological functions, pathological roles, and cellular regulation, highlighting the importance of exploring effective therapeutic interventions to target USP4.

Citing Articles

The Role of Ubiquitin-Proteasome System (UPS) in Asthma Pathology.

Deng S, Ding L, Qian Y, Huang X J Asthma Allergy. 2025; 18:307-330.

PMID: 40046173 PMC: 11881607. DOI: 10.2147/JAA.S490039.

A novel mechanism in regulating drug sensitivity, growth, and apoptosis of bortezomib-resistant multiple myeloma cells: the USP4/KLF2/HMGA2 cascade.

Liu Z, Li X, He Y, Xie F, Zhang Y, Huang M J Orthop Surg Res. 2025; 20(1):220.

PMID: 40022160 PMC: 11871775. DOI: 10.1186/s13018-025-05537-1.

Tenuigenin inhibits osteosarcoma growth via CIP2A/PP2A/NF-κB axis.

Yang S, Liu S, Dai Z Cancer Chemother Pharmacol. 2024; 95(1):15.

PMID: 39739023 DOI: 10.1007/s00280-024-04733-w.

Genetic Variants Associated with Sensitive Skin: A Genome-Wide Association Study in Korean Women.

Kim S, Hong K, Oh M, An S, Han J, Park S Life (Basel). 2024; 14(11).

PMID: 39598151 PMC: 11595562. DOI: 10.3390/life14111352.

Structure, Inhibitors, and Biological Function in Nervous System and Cancer of Ubiquitin-Specific Protease 46.

Thi Pham K, Tran M, Nam L, Pham P, Nguyen T Bioinform Biol Insights. 2024; 18:11779322241285982.

PMID: 39410943 PMC: 11475357. DOI: 10.1177/11779322241285982.

References

Milojevic T, Reiterer V, Stefan E, Korkhov V, Dorostkar M, Ducza E . The ubiquitin-specific protease Usp4 regulates the cell surface level of the A2A receptor. Mol Pharmacol. 2005; 69(4):1083-94. DOI: 10.1124/mol.105.015818. View

Gilchrist C, Baker R . Characterization of the ubiquitin-specific protease activity of the mouse/human Unp/Unph oncoprotein. Biochim Biophys Acta. 2000; 1481(2):297-309. DOI: 10.1016/s0167-4838(00)00134-5. View

Song E, Werner S, Neubauer J, Stegmeier F, Aspden J, Rio D . The Prp19 complex and the Usp4Sart3 deubiquitinating enzyme control reversible ubiquitination at the spliceosome. Genes Dev. 2010; 24(13):1434-47. PMC: 2895201. DOI: 10.1101/gad.1925010. View

Yang J, Xu P, Han L, Guo Z, Wang X, Chen Z . Cutting edge: Ubiquitin-specific protease 4 promotes Th17 cell function under inflammation by deubiquitinating and stabilizing RORγt. J Immunol. 2015; 194(9):4094-7. DOI: 10.4049/jimmunol.1401451. View

Hu M, Li P, Li M, Li W, Yao T, Wu J . Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell. 2003; 111(7):1041-54. DOI: 10.1016/s0092-8674(02)01199-6. View

Jurica M, Moore M . Pre-mRNA splicing: awash in a sea of proteins. Mol Cell. 2003; 12(1):5-14. DOI: 10.1016/s1097-2765(03)00270-3. View

Wertz I, Murray J . Structurally-defined deubiquitinase inhibitors provide opportunities to investigate disease mechanisms. Drug Discov Today Technol. 2019; 31:109-123. DOI: 10.1016/j.ddtec.2019.02.003. View

Frederick A, Rolfe M, Chiu M . The human UNP locus at 3p21.31 encodes two tissue-selective, cytoplasmic isoforms with deubiquitinating activity that have reduced expression in small cell lung carcinoma cell lines. Oncogene. 1998; 16(2):153-65. DOI: 10.1038/sj.onc.1201537. View

Okada K, Ye Y, Taniguchi K, Yoshida A, Akiyama T, Yoshioka Y . Vialinin A is a ubiquitin-specific peptidase inhibitor. Bioorg Med Chem Lett. 2013; 23(15):4328-31. DOI: 10.1016/j.bmcl.2013.05.093. View

10.

Hicke L . Protein regulation by monoubiquitin. Nat Rev Mol Cell Biol. 2001; 2(3):195-201. DOI: 10.1038/35056583. View

11.

Das T, Kim E, Song E . Phosphorylation of USP15 and USP4 Regulates Localization and Spliceosomal Deubiquitination. J Mol Biol. 2019; 431(19):3900-3912. DOI: 10.1016/j.jmb.2019.07.023. View

12.

Vlasschaert C, Xia X, Coulombe J, Gray D . Evolution of the highly networked deubiquitinating enzymes USP4, USP15, and USP11. BMC Evol Biol. 2015; 15:230. PMC: 4624187. DOI: 10.1186/s12862-015-0511-1. View

13.

Zhou F, Zhang X, van Dam H, Ten Dijke P, Huang H, Zhang L . Ubiquitin-specific protease 4 mitigates Toll-like/interleukin-1 receptor signaling and regulates innate immune activation. J Biol Chem. 2012; 287(14):11002-10. PMC: 3322833. DOI: 10.1074/jbc.M111.328187. View

14.

Liu H, Zhang H, Wang X, Tian Q, Hu Z, Peng C . The Deubiquitylating Enzyme USP4 Cooperates with CtIP in DNA Double-Strand Break End Resection. Cell Rep. 2015; 13(1):93-107. DOI: 10.1016/j.celrep.2015.08.056. View

15.

Li F, Sethi G . Targeting transcription factor NF-kappaB to overcome chemoresistance and radioresistance in cancer therapy. Biochim Biophys Acta. 2010; 1805(2):167-80. DOI: 10.1016/j.bbcan.2010.01.002. View

16.

Renatus M, Parrado S, DArcy A, Eidhoff U, Gerhartz B, Hassiepen U . Structural basis of ubiquitin recognition by the deubiquitinating protease USP2. Structure. 2006; 14(8):1293-302. PMC: 7126176. DOI: 10.1016/j.str.2006.06.012. View

17.

Murali S, Aroankins T, Moeller H, Fenton R . The Deubiquitylase USP4 Interacts with the Water Channel AQP2 to Modulate Its Apical Membrane Accumulation and Cellular Abundance. Cells. 2019; 8(3). PMC: 6468601. DOI: 10.3390/cells8030265. View

18.

Zhao Y, Wang F, Gao L, Xu L, Tong R, Lin N . Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Metabolic Dysfunctions in Nonalcoholic Fatty Liver Disease in Mice. Hepatology. 2018; 68(3):897-917. DOI: 10.1002/hep.29889. View

19.

Nottrott S, Urlaub H, Luhrmann R . Hierarchical, clustered protein interactions with U4/U6 snRNA: a biochemical role for U4/U6 proteins. EMBO J. 2002; 21(20):5527-38. PMC: 129076. DOI: 10.1093/emboj/cdf544. View

20.

Wang X, Zhao C, Wang Q, Zeng Q, Feng X, Li L . The p38-interacting protein p38IP suppresses TCR and LPS signaling by targeting TAK1. EMBO Rep. 2020; 21(7):e48035. PMC: 7332986. DOI: 10.15252/embr.201948035. View