MFG-E8 stabilized by deubiquitinase USP14 suppresses cigarette smoke-induced ferroptosis in bronchial epithelial cells

  • Cell Death Dis. 2023 Jan 3;14(1):2. doi: 10.1038/s41419-022-05455-8.
Yanan Cui  1  2  3 ,  Lijuan Luo  1  2  3 ,  Zihang Zeng  1  2  3 ,  Xiangming Liu  1  2  3 ,  Tiao Li  1  2  3 ,  Xue He  1  2  3 ,  Yiming Ma  1  2  3 ,  Weiwei Meng  1  2  3 ,  Huihui Zeng  1  2  3 ,  Yingjiao Long  1  2  3 ,  Dandan Zong  1  2  3 ,  Yan Chen  4  5  6
Affiliations
  • 1. Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
  • 2. Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, China.
  • 3. Diagnosis and Treatment Center of Respiratory Disease, Changsha, Hunan, China.
  • 4. Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China. [email protected].
  • 5. Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, China. [email protected].
  • 6. Diagnosis and Treatment Center of Respiratory Disease, Changsha, Hunan, China. [email protected].
PMID: 36596780 DOI: 10.1038/s41419-022-05455-8
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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