The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis

Kirill Bersuker, Joseph M. Hendricks, Zhipeng Li, Leslie Magtanong, Breanna Ford, Peter H. Tang, Melissa A. Roberts, Bingqi Tong, Thomas J. Maimone, Roberto Zoncu, Michael C. Bassik, Daniel K. Nomura, Scott J. Dixon and James A. Olzmann ()
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Kirill Bersuker: University of California, Berkeley
Joseph M. Hendricks: University of California, Berkeley
Zhipeng Li: University of California, Berkeley
Leslie Magtanong: Stanford University
Breanna Ford: University of California, Berkeley
Peter H. Tang: Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine
Melissa A. Roberts: University of California, Berkeley
Bingqi Tong: University of California, Berkeley
Thomas J. Maimone: University of California, Berkeley
Roberto Zoncu: University of California, Berkeley
Michael C. Bassik: Stanford University School of Medicine
Daniel K. Nomura: University of California, Berkeley
Scott J. Dixon: Stanford University
James A. Olzmann: University of California, Berkeley

Nature, 2019, vol. 575, issue 7784, 688-692

Abstract: Abstract Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols3,4. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions2, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death5. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines6, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR–Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents.

Date: 2019
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DOI: 10.1038/s41586-019-1705-2

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