Journal
REDOX BIOLOGY
Volume 50, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.redox.2022.102232
Keywords
Lipid signaling; Whole body irradiation; Traumatic brain injury; Regulated necrosis; Necroptotic death; Ferroptotic death
Categories
Funding
- NIH [U19AI068021, U01AI156924, U01AI156923, R01NS061817, R01NS076511, F30HL142130, R01GM139297, P41GM103712]
Ask authors/readers for more resources
Ferroptosis and necroptosis are two pro-inflammatory cell death programs that have gained attention for their potential in treating various diseases. This study shows that inhibiting ferroptosis can improve outcomes after irradiation and brain trauma, and the protein PEBP1 plays a crucial role in regulating the switch between necroptosis and ferroptosis.
Ferroptosis and necroptosis are two pro-inflammatory cell death programs contributing to major pathologies and their inhibition has gained attention to treat a wide range of disease states. Necroptosis relies on activation of RIP1 and RIP3 kinases. Ferroptosis is triggered by oxidation of polyunsaturated phosphatidylethanolamines (PUFA-PE) by complexes of 15-Lipoxygenase (15LOX) with phosphatidylethanolamine-binding protein 1 (PEBP1). The latter, also known as RAF kinase inhibitory protein, displays promiscuity towards multiple proteins. In this study we show that RIP3 K51A kinase inactive mice have increased ferroptotic burden and worse outcome after irradiation and brain trauma rescued by anti-ferroptotic compounds Liproxstatin-1 and Ferrostatin 16-86. Given structural homology between RAF and RIP3, we hypothesized that PEBP1 acts as a necroptosis-toferroptosis switch interacting with either RIP3 or 15LOX. Using genetic, biochemical, redox lipidomics and computational approaches, we uncovered that PEBP1 complexes with RIP3 and inhibits necroptosis. Elevated expression combined with higher affinity enables 15LOX to pilfer PEBP1 from RIP3, thereby promoting PUFA-PE oxidation and ferroptosis which sensitizes Rip3K51A/K51A kinase-deficient mice to total body irradiation and brain trauma. This newly unearthed PEBP1/15LOX-driven mechanism, along with previously established switch between necroptosis and apoptosis, can serve multiple and diverse cell death regulatory functions across various human disease states.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available