Overexpression of USP8 inhibits inflammation and ferroptosis in chronic obstructive pulmonary disease by regulating the OTUB1/SLC7A11 signaling pathway
Main Article Content
Keywords
chronic obstructive pulmonary disease, ferroptosis, OTUB1/SLC7A11 pathway, USP8
Abstract
Background: Chronic obstructive pulmonary disease (COPD) is a familiar disease, and owns high morbidity and mortality, which critically damages the health of patients. Ubiquitin-specific peptidase 8 (USP8) is a pivotal protein to join in the regulation of some diseases. In a previous report, it was determined that USP8 expression is down-regulated in LPS-treated BEAS-2B cells, and USP8 restrains inflammatory response and accelerates cell viability. However, the regulatory roles of USP8 on ferroptosis in COPD are rarely reported, and the associated molecular mechanisms keep vague.
Objective: To investigate the regulatory functions of USP8 in COPD progression.
Material and Methods: The lung functions were measured through the Buxco Fine Pointe Series Whole Body Plethysmography (WBP). The Fe level was tested through the Fe assay kit. The protein expressions were assessed through western blot. The levels of tumor necrosis -factor-α, interleukin 6, and interleukin 8 were evaluated through enzyme-linked immunosorbent serologic assay. Cell viability was tested through CCK-8 assay.
Results: In this work, it was discovered that overexpression of USP8 improved lung function in COPD mice. In addition, overexpression of USP8 repressed ferroptosis by regulating glutathione peroxidase 4 and acyl-CoA synthetase long-chain family 4 expressions in COPD mice. Overexpression of USP8 suppressed inflammation in COPD mice. Furthermore, overexpression of USP8 suppressed ferroptosis in COPD cell model. At last, it was verified that overexpression of USP8 accelerated ubiquitin aldehyde-binding protein 1 (OTUB1)/solute carrier family 7 member 11 (SLC7A11) pathway.
Conclusion: This study manifested that overexpression of USP8 restrained inflammation and ferroptosis in COPD by regulating the OTUB1/SLC7A11 signaling pathway. This discovery hinted that USP8 could be a potential target for COPD treatment.
References
2. Ritchie AI, Wedzicha JA. Definition, causes, pathogenesis, and consequences of chronic obstructive pulmonary disease exacerbations. Clin Chest Med. 2020;41(3):421–38. 10.1016/j.ccm.2020.06.007
3. Tantucci C, Modina D. Lung function decline in COPD. Int J Chron Obstruct Pulmon Dis. 2012;7:95–9. 10.2147/COPD.S27480
4. Lu W, Chen X, Liu W, Cai W, Zhu S, Wang Y, et al. XG Boost model predicts acute lung injury after acute pancreatitis. Signa Vitae. 2023;19(5):206–12. 10.22514/sv.2023.087
5. Aghapour M, Raee P, Moghaddam SJ, Hiemstra PS, Heijink IH. Airway epithelial barrier dysfunction in chronic obstructive pulmonary disease: Role of cigarette smoke exposure. Am J Respir Cell Mol Biol. 2018;58(2):157–69. 10.1165/rcmb.2017-0200TR
6. Popovic D, Vucic D, Dikic I. Ubiquitination in disease pathogenesis and treatment. Nat Med. 2014;20(11):1242–53. 10.1038/nm.3739
7. Yang H, Zhang X, Lao M, Sun K, He L, Xu J, et al. Targeting ubiquitin-specific protease 8 sensitizes anti-programmed death-ligand 1 immunotherapy of pancreatic cancer. Cell Death Differ. 2023;30(2):560–75. 10.1038/s41418-022-01102-z
8. Wu S, Lin T, Xu Y. Polymorphic USP8 allele promotes Parkinson's disease by inducing the accumulation of α-synuclein through deubiquitination. Cell Mol Life Sci. 2023;80(12):363. 10.1007/s00018-023-05006-0
9. Zhu Y, Xu J, Hu W, Wang F, Zhou Y, Gong W, et al. Inhibiting USP8 overcomes hepatocellular carcinoma resistance via suppressing receptor tyrosine kinases. Aging (Albany NY). 2021;13(11):14999–5012. 10.18632/aging.203061
10. Duan B, Wang C, Liu Z, Yang X. USP8 is a novel therapeutic target in melanoma through regulating receptor tyrosine kinase levels. Cancer Manag Res. 2021;13:4181–89. 10.2147/CMAR.S300195
11. Zhang Y, Luo Y, Wang Y, Liu H, Yang Y, Wang Q. Effect of deubiquitinase USP8 on hypoxia/reoxygenation-induced inflammation by deubiquitination of TAK1 in renal tubular epithelial cells. Int J Mol Med. 2018;42(6):3467–76. 10.3892/ijmm.2018.3881
12. Liu L, Huan L, Zhang Y, Wei W, Chen Z, Xu D, et al. Ubiquitin-specific protease 8 inhibits lipopolysaccharide-triggered pyroptosis of human bronchial epithelial cells by regulating PI3K/AKT and NF-κB pathways. Allergol Immunopathol (Madr). 2022;50(2):96–103. 10.15586/aei.v50i2.568
13. Xu W, Deng H, Hu S, Zhang Y, Zheng L, Liu M, et al. Role of ferroptosis in lung diseases. J Inflamm Res. 2021;14:2079–90. 10.2147/JIR.S307081
14. Minagawa S, Yoshida M, Araya J, Hara H, Imai H, Kuwano K. Regulated necrosis in pulmonary disease. A focus on necroptosis and ferroptosis. Am J Respir Cell Mol Biol. 2020;62(5): 554–62. 10.1165/rcmb.2019-0337TR
15. Xu H, Niu H, Wang H, Lin J, Yao J. Knockdown of RTEL1 alleviates chronic obstructive pulmonary disease by modulating M1, M2 macrophage polarization and inflammation. COPD. 2024;21(1):2316607. 10.1080/15412555.2024.2316607
16. Chang C, Huang K, Xu X, Duan R, Yu T, Chu X, et al. MiR-23a-5p alleviates chronic obstructive pulmonary disease through targeted regulation of RAGE-ROS pathway. Respir Res. 2024;25(1):93. 10.1186/s12931-024-02736-y
17. Luo L, Zeng Z, Li T, Liu X, Cui Y, Tao Y, et al. TET2 stabilized by deubiquitinase USP21 ameliorates cigarette smoke-induced apoptosis in airway epithelial cells. iScience. 2024;27(3):109252. 10.1016/j.isci.2024.109252
18. Dong L, Wang Y, Chen H, Li Z, Xu X, Zhou J, et al. MTOR suppresses cigarette smoke-induced airway inflammation and MMP12 expression in macrophage in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2024;19:269–79. 10.2147/COPD.S426333
19. Chen X, Li J, Kang R, Klionsky DJ, Tang D. Ferroptosis: Machinery and regulation. Autophagy. 2021;17(9):2054–81. 10.1080/15548627.2020.1810918
20. Liu X, Ma Y, Luo L, Zong D, Li H, Zeng Z, et al. Dihydroquercetin suppresses cigarette smoke induced ferroptosis in the pathogenesis of chronic obstructive pulmonary disease by activating Nrf2-mediated pathway. Phytomedicine. 2022;96:153894. 10.1016/j.phymed.2021.153894
21. Cui Y, Luo L, Zeng Z, Liu X, Li T, He X, et al. MFG-E8 stabilized by deubiquitinase USP14 suppresses cigarette smoke-induced ferroptosis in bronchial epithelial cells. Cell Death Dis. 2023;14(1):2. 10.1038/s41419-022-05455-8
22. Zeng Z, Li T, Liu X, Ma Y, Luo L, Wang Z, et al. DNA dioxygenases TET2 deficiency promotes cigarette smoke induced chronic obstructive pulmonary disease by inducing ferroptosis of lung epithelial cell. Redox Biol. 2023;67:102916. 10.1016/j.redox.2023.102916
23. Tang J, Long G, Xiao L, Zhou L, et al. USP8 positively regulates hepatocellular carcinoma tumorigenesis and confers ferroptosis resistance through β-catenin stabilization. Cell Death Dis. 2023;14(6):360. 10.1038/s41419-023-05747-7
24. Liu L, Zheng B, Luo M, Du J, Yang F, Huang C, et al. Suppression of USP8 sensitizes cells to ferroptosis via SQSTM1/p62--mediated ferritinophagy. Protein Cell. 2023;14(3):230–4. 10.1093/procel/pwac004
25. Liu T, Jiang L, Tavana O, Gu W. The deubiquitylase OTUB1 mediates ferroptosis via stabilization of SLC7A11. Cancer Res. 2019;79(8):1913–24. 10.1158/0008-5472.CAN-18-3037
26. Hu P, Xu Y, Jiang Y, Huang J, Liu Y, Wang D, et al. The mechanism of the imbalance between proliferation and ferroptosis in pulmonary artery smooth muscle cells based on the-activation of SLC7A11. Eur J Pharmacol. 2022;928:175093. 10.1016/j.ejphar.2022.175093
27. Tang J, Long G, Hu K, Xiao D, Liu S, Xiao L, et al. Targeting USP8 inhibits O-GlcNAcylation of SLC7A11 to promote ferroptosis of hepatocellular carcinoma via stabilization of OGT. Adv Sci (Weinh). 2023;10(33):e2302953. 10.1002/advs.202302953
Article Sidebar
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.