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http://dx.doi.org/10.5352/JLS.2022.32.6.476

Pathophysiological Functions of Deubiquitinating Enzymes in Obesity and Related Metabolic Diseases  

Lee, Seul Gi (Department of Immunology, School of Medicine, Keimyung University)
Kwon, Taeg Kyu (Department of Immunology, School of Medicine, Keimyung University)
Publication Information
Journal of Life Science / v.32, no.6, 2022 , pp. 476-481 More about this Journal
Abstract
Ubiquitin signaling regulates virtually all aspects of eukaryotic biology and dynamic processes in which protein substrates are modified by ubiquitin. To regulate these processes, deubiquitinating enzymes (DUBs) cleave ubiquitin or ubiquitin-like proteins from these substrates. DUBs have been implicated in the pathogenesis of cancer, leading to the development of increasing numbers of small-molecule DUB inhibitors. On the other hand, recent studies have focused on the function of DUBs in metabolic diseases such as obesity, diabetes, and fatty liver diseases. DUBs play a positive or negative role in the progression and development of metabolic diseases. Their involvement in cell pathology and regulation of major transcription factors in metabolic syndrome has been examined in vitro and in animal and human biopsies. UCH, USP7, and USP19 were linked to adipocyte differentiation, body weight gain, and insulin resistance in genetic or diet-induced obesity. CYLD, USP4, and USP18 were found to be closely associated with fatty liver diseases. In addition, these liver diseases were accompanied by body weight change in certain cases. Collectively, in this review, we discuss the current understanding of DUBs in metabolic diseases with a particular focus on obesity. We also provide basic knowledge and regulatory mechanisms of DUBs and suggest these enzymes as therapeutic targets for metabolic diseases.
Keywords
Adipocytes; deubiquitinating enzymes; metabolic diseases; obesity; ubiquitin;
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1 Akoumianakis, I. and Sanna, F. 2019. Adipose tissue-derived WNT5A regulates vascular redox signaling in obesity via USP17/RAC1-mediated activation of nadph oxidases. Sci. Transl. Med. 11, 510.
2 An, S., Zhao L. P., Shen, L. J., Wang, S., Zhang, K., Qi Y., Zheng, J. ,Zhang, X. J., Zhu, X. Y., Bao, R., Yang, L., Lu, Y. X., She, Z. G. and Tang, Y. D. 2017. USP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity. Hepatology 66, 1866-1884.   DOI
3 Darling, S., Fielding, A. B., Sabat-Pospiech, D., Prior, I. A. and Coulson, J. M. 2017. Regulation of the cell cycle and centrosome biology by deubiquitylases. Biochem. Soc. Trans. 45, 1125-1136.   DOI
4 Gao, Y., Koppen, A., Rakhshandehroo, M., Tasdelen, I., van de Graaf, S. F., van Loosdregt, J., van Beekum, O., Hamers, N., van Leenen, D., Berkers, C. R., Berger, R., Holstege, F. C., Coffer, P. J., Brenkman, A. B., Ovaa, H. and Kalkhoven, E. 2013. Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60. Nat. Commun. 4, 2656.   DOI
5 Jacq, X., Kemp, M., Martin, N. M. and Jackson, S. P. 2013. Deubiquitylating enzymes and DNA damage response pathways. Cell Biochem. Biophys. 67, 25-43.   DOI
6 Kwasna, D., Abdul Rehman, S. A., Natarajan, J., Matthews, S., Madden, R., De Cesare, V., Weidlich, S., Virdee, S., Ahel, I., Gibbs-Seymour, I. and Kulathu, Y. 2018. Discovery and characterization of ZUFSP/ZUP1, a distinct deubiquitinase class important for genome stability. Mol. Cell 70, 150-164.e156.   DOI
7 Li, S., Zhang, H. and Wei, X. 2021. Roles and mechanisms of deubiquitinases (DUBs) in breast cancer progression and targeted drug discovery. Life (Basel) 11, 9.
8 Liu, B., Jiang, S., Li, M., Xiong, X., Zhu, M., Li, D., Zhao, L., Qian, L., Zhai, L. and Li, J. 2018. Proteome-wide analysis of USP14 substrates revealed its role in hepatosteatosis via stabilization of FASN. Nat. Commun. 9, 4770.   DOI
9 Sadler, J. B. A., Lamb, C. A., Welburn, C. R., Adamson, I. S., Kioumourtzoglou, D., Chi, N. W., Gould, G. W. and Bryant, N. J. 2019. The deubiquitinating enzyme USP25 binds tankyrase and regulates trafficking of the facilitative glucose transporter GLUT4 in adipocytes. Sci. Rep. 9, 4710.   DOI
10 Seki, E. 2014. TAK1-dependent autophagy: A suppressor of fatty liver disease and hepatic oncogenesis. Mol. Cell Oncol. 1, e968507.   DOI
11 Suzuki, M., Setsuie, R. and Wada, K. 2009. Ubiquitin carboxyl-terminal hydrolase l3 promotes insulin signaling and adipogenesis. Endocrinology 150, 5230-5239.   DOI
12 Tang, Y., Lv, L., Li, W., Zhang, X., Jiang, Y., Ge, W. and Zhou, Y. 2017. Protein deubiquitinase USP7 is required for osteogenic differentiation of human adipose-derived stem cells. Stem. Cell. Res. Ther. 8, 186.   DOI
13 Yan, F. J., Zhang, X. J., Wang, W. X., Ji, Y. X., Wang, P. X., Yang, Y., Gong, J., Shen, L. J., Zhu, X. Y., Huang, Z. and Li, H. 2017. The E3 ligase tripartite motif 8 targets TAK1 to promote insulin resistance and steatohepatitis. Hepatology 65, 1492-1511.   DOI
14 Coyne, E. S., Bedard, N., Gong, Y. J., Faraj, M., Tchernof, A. and Wing, S. S. 2019. The deubiquitinating enzyme USP19 modulates adipogenesis and potentiates high-fat-diet-induced obesity and glucose intolerance in mice. Diabetologia 62, 136-146.   DOI
15 Ghemrawi, R., Battaglia-Hsu, S. F. and Arnold, C. 2018. Endoplasmic reticulum stress in metabolic disorders. Cells 7, 63.   DOI
16 Lim, K. H., Choi, J. H., Park, J. H., Cho, H. J., Park, J. J., Lee, E. J., Li L., Choi, Y. K. and Baek, K. H. 2016. Ubiquitin specific protease 19 involved in transcriptional repression of retinoic acid receptor by stabilizing CORO2A. Oncotarget 7, 34759-34772.   DOI
17 Zhu, S., Hou, S., Lu, Y., Sheng, W., Cui, Z., Dong, T., Feng, H. and Wan, Q. 2021. USP36-mediated deubiquitination of DOCK4 contributes to the diabetic renal tubular epithelial cell injury via WNT/β-catenin signaling pathway. Front. Cell. Dev. Biol. 9, 638477.   DOI
18 Mennerich, D., Kubaichuk, K. and Kietzmann, T. 2019. DUBs, hypoxia, and cancer. Trends Cancer 5, 632-653.   DOI
19 Mukherjee, A., Morales-Scheihing, D., Butler, P. C. and Soto, C. 2015. Type 2 diabetes as a protein misfolding disease. Trends. Mol. Med. 21, 439-449.   DOI
20 Ji, Y. X. and Huang, Z. 2018. The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic steatohepatitis. Nat. Med. 24, 213-223.   DOI
21 Longo, M., Zatterale, F., Naderi, J., Parrillo, L., Formisano, P., Raciti, G. A., Beguinot, F. and Miele, C. 2019. Adipose tissue dysfunction as determinant of obesity-associated metabolic complications. Int. J. Mol. Sci. 20, 9.   DOI
22 Mevissen, T. E. T. and Komander, D. 2017. Mechanisms of deubiquitinase specificity and regulation. Annu. Rev. Biochem. 86, 159-192.   DOI
23 Poondla, N., Chandrasekaran, A. P., Kim, K. S. and Ramakrishna, S. 2019. Deubiquitinating enzymes as cancer biomarkers: New therapeutic opportunities? BMB Rep. 52, 181-189.   DOI
24 Sharma, A., Alswillah, T., Singh, K., Chatterjee, P., Willard, B., Venere, M., Summers, M. K. and Almasan, A. 2018. USP14 regulates DNA damage repair by targeting RNF 168-dependent ubiquitination. Autophage 14, 1976-1990.   DOI
25 Urbe, S., Liu, H., Hayes, S. D., Heride, C., Rigden, D. J. and Clague, M. J. 2012. Systematic survey of deubiquitinase localization identifies USP21 as a regulator of centrosomeand microtubule-associated functions. Mol. Biol. Cell 23, 1095-1103.   DOI
26 Liu, B., Zhang, Z., Hu, Y., Lu, Y., Li, D., Liu, J., Liao, S., Hu, M., Wang, Y., Zhang, D., Chen, Y., Qian, Q., Lv, X., Wu, D., Tan, M., Hu, C., Xiong, X. and Li, X. 2019. Sustained er stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP 14. Proc. Natl. Acad. Sci. USA. 116, 21732-21738.   DOI
27 Gonidas, C., Hadweh, P. and Mosialos, G. 2022. Deubiquitinating enzymes at the crossroads of lipid metabolism and cancer. J. Biol. Res.-Thessalon. 29, 1.