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

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.

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

“… 482 COPD Ubiquitination MFG-E8 Cigarette smoke-induced diminished USP14 expression leads to the proteasomal degradation of MFG-E8, which aggravates bronchial epithelial cell ferroptosis. 483 Pulmonary fibrosis Methylation GPX4 and FSP1 Upregulation de novo methylation regulator UHRF1 sensitively elevates CpG site methylation levels in promoters of both GPX4 and FSP1 genes and induces the epigenetic repression of both genes, subsequently leading to ferroptosis in chemically interfered AEC2 cells. 630 Pulmonary epithelial senescence Acetylation USP3/SIRT3/p53/SLC7A11 PM2.5 triggers pulmonary epithelial senescence and ferroptosis through decreasing USP3, by which leads to SIRT3 degradation via ubiquition proteasome pathway, thereby increasing p53 acetylation, which transcriptionally activates p21 and inhibits SLC7A11.…”

“… 482 Cigarette smoke-induced USP14 downregulation aggravates bronchial epithelial cell ferroptosis through proteasomal degradation of MFG-E8. 483 …”

“… 598 COPD rhMFG-E8 Ubiquitination MFG-E8 rhMFG-E8 ameliorates ferroptosis induced by cigarette smoke extract in BEAS-2B cells and HBE cells. 483 Diabetic nephropathy Germacrone - - Germacrone inhibits DN through inhibiting ferroptosis via mmu_circRNA_0000309 silence or miR-188-3p mimics abrogated the antiapoptosis and anti-injury effects of germacrone through aggravating mitochondria damage, and elevating reactive oxygen species and ferroptosis-related protein levels. 486 Renal IRI IU1 Ubiquitination USP14 IU1, a small molecule inhibitor of USP14 and NAC effectively alleviated renal injury of I/R mice.…”

Inhibitory Effect of P22077 on Airway Inflammation in Rats with COPD and Its Mechanism

“… 6 , 7 Palazon-Riquelme et al and Cui et al 8 , 9 showed that the deubiquitinating enzymes USP7 and USP47 are involved in the activation of inflammatory vesicles in macrophages. Juliana et al 10 have shown that the regulation of inflammatory vesicles by the ubiquitination system has a role in the development and progression of COPD. Song et al 11 found that the deubiquitinating enzyme inhibitor P22077, an inhibitor of both USP7 and USP47, can block inflammatory vesicles for anti-inflammatory purposes.…”

Ferroptosis in chronic obstructive pulmonary disease: From cellular mechanisms to therapeutic applications

“…[ 6 ] Milk fat globule epidermal growth factor 8 (MFG-E8) has been identified as a mitigator of CSE-induced ferroptosis in BECs, and ubiquitin specific peptidase 14 (USP14) stabilizes MFG-E8 protein, suppressing CS-induced ferroptosis. [ 7 ] m 6 A-modified circular RNA SAV1 ( circSAV1 ) forms an RNA–protein complex that promotes the translation of iron-responsive element binding protein 2 ( IREB2 ) mRNA. Increased IREB2 levels disrupt iron homeostasis, resulting in the accumulation of a labile iron pool and lipid peroxidation, contributing to ferroptosis in epithelial cells.…”