Unraveling the Immune Regulatory Functions of USP5: Implications for Disease Therapy

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2024 Jun 27

PMID 38927085

Authors

Jinyi Gu

Changshun Chen

Pu He

Yunjie Du

Bingdong Zhu

Affiliations

Soon will be listed here.

Abstract

Ubiquitin-specific protease 5 (USP5) belongs to the ubiquitin-specific protease (USP) family, which uniquely recognizes unanchored polyubiquitin chains to maintain the homeostasis of monoubiquitin chains. USP5 participates in a wide range of cellular processes by specifically cleaving isopeptide bonds between ubiquitin and substrate proteins or ubiquitin itself. In the process of immune regulation, USP5 affects important cellular signaling pathways, such as NF-κB, Wnt/β-catenin, and IFN, by regulating ubiquitin-dependent protein degradation. These pathways play important roles in immune regulation and inflammatory responses. In addition, USP5 regulates the activity and function of immunomodulatory signaling pathways via the deubiquitination of key proteins, thereby affecting the activity of immune cells and the regulation of immune responses. In the present review, the structure and function of USP5, its role in immune regulation, and the mechanism by which USP5 affects the development of diseases by regulating immune signaling pathways are comprehensively overviewed. In addition, we also introduce the latest research progress of targeting USP5 in the treatment of related diseases, calling for an interdisciplinary approach to explore the therapeutic potential of targeting USP5 in immune regulation.

References

Komander D, Clague M, Urbe S . Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol. 2009; 10(8):550-63. DOI: 10.1038/nrm2731. View

Nakano T, Katsuki S, Chen M, Decano J, Halu A, Ho Lee L . Uremic Toxin Indoxyl Sulfate Promotes Proinflammatory Macrophage Activation Via the Interplay of OATP2B1 and Dll4-Notch Signaling. Circulation. 2018; 139(1):78-96. PMC: 6311723. DOI: 10.1161/CIRCULATIONAHA.118.034588. View

Liu T, Zhang L, Joo D, Sun S . NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017; 2. PMC: 5661633. DOI: 10.1038/sigtrans.2017.23. View

Clague M, Urbe S, Komander D . Breaking the chains: deubiquitylating enzyme specificity begets function. Nat Rev Mol Cell Biol. 2019; 20(6):338-352. DOI: 10.1038/s41580-019-0099-1. View

Shi J, Liu Y, Xu X, Zhang W, Yu T, Jia J . Deubiquitinase USP47/UBP64E Regulates β-Catenin Ubiquitination and Degradation and Plays a Positive Role in Wnt Signaling. Mol Cell Biol. 2015; 35(19):3301-11. PMC: 4561727. DOI: 10.1128/MCB.00373-15. View

Avvakumov G, Walker J, Xue S, Allali-Hassani A, Asinas A, Nair U . Two ZnF-UBP domains in isopeptidase T (USP5). Biochemistry. 2012; 51(6):1188-98. PMC: 8391072. DOI: 10.1021/bi200854q. View

Luo X, Xi J, Liu Z, Long Y, Li L, Luo Z . Proinflammatory Effects of Ubiquitin-Specific Protease 5 (USP5) in Rheumatoid Arthritis Fibroblast-Like Synoviocytes. Mediators Inflamm. 2020; 2020:8295149. PMC: 7085372. DOI: 10.1155/2020/8295149. 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

Qian G, Zhu L, Huang C, Liu Y, Ren Y, Ding Y . Ubiquitin specific protease 5 negatively regulates the IFNs-mediated antiviral activity via targeting SMURF1. Int Immunopharmacol. 2020; 87:106763. DOI: 10.1016/j.intimp.2020.106763. View

10.

Ban T, Sato G, Nishiyama A, Akiyama A, Takasuna M, Umehara M . Lyn Kinase Suppresses the Transcriptional Activity of IRF5 in the TLR-MyD88 Pathway to Restrain the Development of Autoimmunity. Immunity. 2016; 45(2):319-32. DOI: 10.1016/j.immuni.2016.07.015. View

11.

Duan T, Feng Y, Du Y, Xing C, Chu J, Ou J . USP3 plays a critical role in the induction of innate immune tolerance. EMBO Rep. 2023; 24(12):e57828. PMC: 10702844. DOI: 10.15252/embr.202357828. View

12.

Kapuria V, Peterson L, Showalter H, Kirchhoff P, Talpaz M, Donato N . Protein cross-linking as a novel mechanism of action of a ubiquitin-activating enzyme inhibitor with anti-tumor activity. Biochem Pharmacol. 2011; 82(4):341-9. DOI: 10.1016/j.bcp.2011.05.012. View

13.

Xie X, Matsumoto S, Endo A, Fukushima T, Kawahara H, Saeki Y . Deubiquitylases USP5 and USP13 are recruited to and regulate heat-induced stress granules through their deubiquitylating activities. J Cell Sci. 2018; 131(8). DOI: 10.1242/jcs.210856. View

14.

Harrigan J, Jacq X, Martin N, Jackson S . Deubiquitylating enzymes and drug discovery: emerging opportunities. Nat Rev Drug Discov. 2017; 17(1):57-78. PMC: 7097658. DOI: 10.1038/nrd.2017.152. View

15.

Dayal S, Sparks A, Jacob J, Allende-Vega N, Lane D, Saville M . Suppression of the deubiquitinating enzyme USP5 causes the accumulation of unanchored polyubiquitin and the activation of p53. J Biol Chem. 2008; 284(8):5030-41. PMC: 2696100. DOI: 10.1074/jbc.M805871200. View

16.

Wang C, Chen G, Chien C . The deubiquitinase Leon/USP5 regulates ubiquitin homeostasis during Drosophila development. Biochem Biophys Res Commun. 2014; 452(3):369-75. DOI: 10.1016/j.bbrc.2014.08.069. View

17.

Chen Q, Su J, Chen X . Role of ubiquitin-specific protease 5 in the inflammatory response of chronic periodontitis. Oral Dis. 2021; 29(3):1234-1241. DOI: 10.1111/odi.14114. View

18.

Wang S, Juan J, Zhang Z, Du Y, Xu Y, Tong J . Inhibition of the deubiquitinase USP5 leads to c-Maf protein degradation and myeloma cell apoptosis. Cell Death Dis. 2017; 8(9):e3058. PMC: 5636991. DOI: 10.1038/cddis.2017.450. View

19.

Shang Y, Smith S, Hu X . Role of Notch signaling in regulating innate immunity and inflammation in health and disease. Protein Cell. 2016; 7(3):159-74. PMC: 4791423. DOI: 10.1007/s13238-016-0250-0. View

20.

Zheng Y, Wang L, Niu X, Guo Y, Zhao J, Li L . EOAI, a ubiquitin-specific peptidase 5 inhibitor, prevents non-small cell lung cancer progression by inducing DNA damage. BMC Cancer. 2023; 23(1):28. PMC: 9826599. DOI: 10.1186/s12885-023-10506-0. View