MFG-E8 Stabilized by Deubiquitinase USP14 Suppresses Cigarette Smoke-induced Ferroptosis in Bronchial Epithelial Cells

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2023 Jan 3

PMID 36596780

Authors

Yanan Cui

Lijuan Luo

Zihang Zeng

Xiangming Liu

Tiao Li

Xue He

Yiming Ma

Weiwei Meng

Huihui Zeng

Yingjiao Long

Dandan Zong

Yan Chen

Affiliations

Soon will be listed here.

Abstract

Milk fat globule epidermal growth factor 8 (MFG-E8) participates in a range of cellular processes, including reducing apoptosis and oxidative stress. However, its protective activity against cigarette smoke-induced ferroptosis in the pathogenesis of the chronic obstructive pulmonary disease (COPD) and the modulation of MFG-E8 remain unclear. Here, we showed that cigarette smoke diminished MFG-E8 protein levels but had no significant effect on its mRNA levels in lung tissues of humans and mice and in two human bronchial epithelial cell lines. MFG-E8 could attenuate ferroptosis induced by cigarette smoke extract (CSE) in vivo and in vitro. We identified ubiquitin-specific protease 14 (USP14) as a deubiquitinase of MFG-E8 in human bronchial epithelial cells. USP14 interacted with, deubiquitinated and stabilized MFG-E8. Furthermore, USP14 inhibited CSE-induced MFG-E8 proteasomal degradation. USP14 expression downregulated by CSE decreased MFG-E8 abundance and further reduced the antiferroptotic effect of MFG-E8. These findings suggest that USP14 is an essential regulator of MFG-E8 through the proteasomal pathway and that the USP14/MFG-E8 axis plays a critical role in regulating CSE-induced ferroptosis of bronchial epithelial cells.

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References

Zhang S, Xie J, Su B, Li J, Hu N, Chen J . MFG-E8, a clearance glycoprotein of apoptotic cells, as a new marker of disease severity in chronic obstructive pulmonary disease. Braz J Med Biol Res. 2015; 48(11):1032-8. PMC: 4671530. DOI: 10.1590/1414-431X20154730. View

Wang Y, Luo G, Chen J, Jiang R, Zhu J, Hu N . Cigarette smoke attenuates phagocytic ability of macrophages through down-regulating Milk fat globule-EGF factor 8 (MFG-E8) expressions. Sci Rep. 2017; 7:42642. PMC: 5307389. DOI: 10.1038/srep42642. View

Hirschhorn T, Stockwell B . The development of the concept of ferroptosis. Free Radic Biol Med. 2018; 133:130-143. PMC: 6368883. DOI: 10.1016/j.freeradbiomed.2018.09.043. View

Wang J, Wu J, Zhu X, Chen J, Zhao J, Xu Y . Absence of the MFG-E8 gene prevents hypoxia-induced pulmonary hypertension in mice. J Cell Physiol. 2020; 236(1):587-600. PMC: 7689852. DOI: 10.1002/jcp.29885. View

Huang W, Jiao J, Liu J, Huang M, Hu Y, Ran W . MFG-E8 accelerates wound healing in diabetes by regulating "NLRP3 inflammasome-neutrophil extracellular traps" axis. Cell Death Discov. 2020; 6:84. PMC: 7484765. DOI: 10.1038/s41420-020-00318-7. View

Song H, Tao L, Chen C, Pan L, Hao J, Ni Y . USP17-mediated deubiquitination and stabilization of HDAC2 in cigarette smoke extract-induced inflammation. Int J Clin Exp Pathol. 2015; 8(9):10707-15. PMC: 4637596. View

Schwartz A, Ciechanover A . Targeting proteins for destruction by the ubiquitin system: implications for human pathobiology. Annu Rev Pharmacol Toxicol. 2008; 49:73-96. DOI: 10.1146/annurev.pharmtox.051208.165340. View

Fujiwara C, Motegi S, Ohira A, Yamaguchi S, Sekiguchi A, Yasuda M . The significance of tumor cells-derived MFG-E8 in tumor growth of angiosarcoma. J Dermatol Sci. 2019; 96(1):18-25. DOI: 10.1016/j.jdermsci.2019.08.005. View

Stintzing S, Lenz H . Molecular pathways: turning proteasomal protein degradation into a unique treatment approach. Clin Cancer Res. 2014; 20(12):3064-70. PMC: 4703318. DOI: 10.1158/1078-0432.CCR-13-3175. View

10.

Dixon S, Lemberg K, Lamprecht M, Skouta R, Zaitsev E, Gleason C . Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149(5):1060-72. PMC: 3367386. DOI: 10.1016/j.cell.2012.03.042. View

11.

Wang F, Ning S, Yu B, Wang Y . USP14: Structure, Function, and Target Inhibition. Front Pharmacol. 2022; 12:801328. PMC: 8766727. DOI: 10.3389/fphar.2021.801328. View

12.

Li J, Xu X, Cai X, Weng Y, Wang Y, Shen Q . Milk Fat Globule-Epidermal Growth Factor-Factor 8 Reverses Lipopolysaccharide-Induced Microglial Oxidative Stress. Oxid Med Cell Longev. 2019; 2019:2601394. PMC: 6436360. DOI: 10.1155/2019/2601394. View

13.

Yoshida M, Minagawa S, Araya J, Sakamoto T, Hara H, Tsubouchi K . Involvement of cigarette smoke-induced epithelial cell ferroptosis in COPD pathogenesis. Nat Commun. 2019; 10(1):3145. PMC: 6637122. DOI: 10.1038/s41467-019-10991-7. View

14.

Shen M, Schmitt S, Buac D, Dou Q . Targeting the ubiquitin-proteasome system for cancer therapy. Expert Opin Ther Targets. 2013; 17(9):1091-108. PMC: 3773690. DOI: 10.1517/14728222.2013.815728. View

15.

Yi Y . Functional Role of Milk Fat Globule-Epidermal Growth Factor VIII in Macrophage-Mediated Inflammatory Responses and Inflammatory/Autoimmune Diseases. Mediators Inflamm. 2016; 2016:5628486. PMC: 4939324. DOI: 10.1155/2016/5628486. View

16.

Li T, He X, Luo L, Zeng H, Ren S, Chen Y . F-Box Protein FBXW17-Mediated Proteasomal Degradation of Protein Methyltransferase PRMT6 Exaggerates CSE-Induced Lung Epithelial Inflammation and Apoptosis. Front Cell Dev Biol. 2021; 9:599020. PMC: 8095709. DOI: 10.3389/fcell.2021.599020. View

17.

Liu X, Ma Y, Luo L, Zong D, Li H, Zeng Z . Dihydroquercetin suppresses cigarette smoke induced ferroptosis in the pathogenesis of chronic obstructive pulmonary disease by activating Nrf2-mediated pathway. Phytomedicine. 2021; 96:153894. DOI: 10.1016/j.phymed.2021.153894. View

18.

Xu D, Shan B, Sun H, Xiao J, Zhu K, Xie X . USP14 regulates autophagy by suppressing K63 ubiquitination of Beclin 1. Genes Dev. 2016; 30(15):1718-30. PMC: 5002977. DOI: 10.1101/gad.285122.116. View

19.

Huang W, Wu J, Yang H, Xiong Y, Jiang R, Cui T . Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage. Cell Death Differ. 2016; 24(2):263-275. PMC: 5299708. DOI: 10.1038/cdd.2016.115. View

20.

He Z, Chen P, Chen Y, He S, Ye J, Zhang H . Comparison between cigarette smoke-induced emphysema and cigarette smoke extract-induced emphysema. Tob Induc Dis. 2015; 13(1):6. PMC: 4374374. DOI: 10.1186/s12971-015-0033-z. View