PEBP1 acts as a rheostat between prosurvival autophagy and ferroptotic death in asthmatic epithelial cells

Abstract

Temporally harmonized elimination of damaged or unnecessary organelles and cells is a prerequisite of health. Under Type 2 inflammatory conditions, human airway epithelial cells (HAECs) generate proferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamines (HpETE-PEs) as proximate death signals. Production of 15-HpETE-PE depends on activation of 15-lipoxygenase-1 (15LO1) in complex with PE-binding protein-1 (PEBP1). We hypothesized that cellular membrane damage induced by these proferroptotic phospholipids triggers compensatory prosurvival pathways, and in particular autophagic pathways, to prevent cell elimination through programmed death. We discovered that PEBP1 is pivotal to driving dynamic interactions with both proferroptotic 15LO1 and the autophagic protein microtubule-associated light chain-3 (LC3). Further, the 15LO1–PEBP1-generated ferroptotic phospholipid, 15-HpETE-PE, promoted LC3-I lipidation to stimulate autophagy. This concurrent activation of autophagy protects cells from ferroptotic death and release of mitochondrial DNA. Similar findings are observed in Type 2 Hi asthma, where high levels of both 15LO1–PEBP1 and LC3-II are seen in HAECs, in association with low bronchoalveolar lavage fluid mitochondrial DNA and more severe disease. The concomitant activation of ferroptosis and autophagy by 15LO1–PEBP1 complexes and their hydroperoxy-phospholipids reveals a pathobiologic pathway relevant to asthma and amenable to therapeutic targeting.

Ferroptosis: molecular mechanisms and health implications

“…As a possibility, changes in membrane PEBP1-dependent lipid signals determine the dual function of autophagy in ferroptosis. 112 , 122 …”

Ammonium Ferric Citrate induced Ferroptosis in Non-Small-Cell Lung Carcinoma through the inhibition of GPX4-GSS/GSR-GGT axis activity

“…It was speculated that autophagy is an indispensable physiological phenomenon in the process of ferroptosis in cells 36 .Wei et al reported that arsenic could damage mitochondria and induce pancreatic dysfunction and ferroptosis via mitochondrial ROS and autophagy-lysosomal disorder 37 . However, Zhao also found that 15-lipoxygenase-1-PE-binding protein-1-generated ferroptotic phospholipids and 15-proferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamines promoted LC3-I lipidation to stimulate autophagy 38 . This concurrent activation of autophagy protects cells from ferroptotic death and the release of mitochondrial DNA.…”

“…This concurrent activation of autophagy protects cells from ferroptotic death and the release of mitochondrial DNA. Therefore, when there is an excess of iron ions, the autophagy rate decreases, leading to ferroptotic death 38 . In addition, Liu et al provided novel evidence that the interplay between the signals of the mechanistic target of rapamycin kinase and GPX4 modulates autophagy-dependent ferroptosis in human pancreatic cancer cells, and the down-regulation for GPX4 enhances the anti-cancer activity of rapamycin in vitro or in vivo by promoting ferroptosis and suppressing autophagy 39 .…”

PEBP regulates balance between apoptosis and autophagy, enabling coexistence of arbovirus and insect vector

“…There are strong indications that PEBPs are involved in regulating autophagy-associated degradation (Noh et al, 2016; Zhao et al, 2020a). Human PEBP1 is reported to interact with LC3-interacting region (LIR) motif of PE-unconjugated LC3B, the homolog of ATG8 in mammals.…”

“…The complex prevents the initiation of autophagy that is independent of MAPK signaling pathway (Noh et al, 2016). Moreover, human PEBP4 is co-localized with the lysosome, suggesting its potential role in regulation of degradation (Zhao et al, 2020a). Similarly, whitefly PEBP4 predictably consists of LIR motifs, capable of sequestering ATG8.…”