PKC?II phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis.
The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain obscure. Here we identify PKC?II as a critical contributor of ferroptosis through independent genome-wide CRISPR-Cas9 and kinase inhibitor library screening. Our results ... show that PKC?II senses the initial lipid peroxides and amplifies lipid peroxidation linked to ferroptosis through phosphorylation and activation of ACSL4. Lipidomics analysis shows that activated ACSL4 catalyses polyunsaturated fatty acid-containing lipid biosynthesis and promotes the accumulation of lipid peroxidation products, leading to ferroptosis. Attenuation of the PKC?II-ACSL4 pathway effectively blocks ferroptosis in vitro and impairs ferroptosis-associated cancer immunotherapy in vivo. Our results identify PKC?II as a sensor of lipid peroxidation, and the lipid peroxidation-PKC?II-ACSL4 positive-feedback axis may provide potential targets for ferroptosis-associated disease treatment.
Mesh Terms:
Animals, CRISPR-Cas Systems, Cell Line, Tumor, Coenzyme A Ligases, Ferroptosis, Gene Knockout Techniques, Humans, Immunotherapy, Lipid Peroxidation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Phosphorylation, Protein Kinase C beta
Animals, CRISPR-Cas Systems, Cell Line, Tumor, Coenzyme A Ligases, Ferroptosis, Gene Knockout Techniques, Humans, Immunotherapy, Lipid Peroxidation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Phosphorylation, Protein Kinase C beta
Nat Cell Biol
Date: Jan. 01, 2022
PubMed ID: 35027735
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