Chaperone-mediated autophagy is involved in the execution of ferroptosis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 8; pp. 2996 - 3005
• Main Authors: Wu, Zheming, Geng, Yang, Lu, Xiaojuan, Shi, Yuying, Wu, Guowei, Zhang, Mengmeng, Shan, Bing, Pan, Heling, Yuan, Junying
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.02.2019
• Series: PNAS Plus
• Subjects: Activation; Apoptosis - drug effects; Apoptosis - genetics; Autophagy; Autophagy - drug effects; Autophagy - genetics; Biological Sciences; Caspase; Caspases - genetics; Cell death; Cell Death - drug effects; Cell Death - genetics; Death receptors; Depletion; Ferroptosis; Glutathione; Glutathione peroxidase; Glutathione Peroxidase - genetics; Heat shock proteins; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - genetics; Hsp90 protein; Humans; Iron - metabolism; Kinases; Ligands; Lipid Peroxides - genetics; Lipid Peroxides - metabolism; Lipids; Lysosomal-Associated Membrane Protein 2 - genetics; Membrane proteins; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Molecular modelling; Necroptosis; Necrosis - genetics; Peroxidase; Peroxides; Phagocytosis; Phospholipid Hydroperoxide Glutathione Peroxidase; Piperazines - metabolism; PNAS Plus; Reactive Oxygen Species - metabolism; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptors; Tumor Necrosis Factor-alpha - genetics; Tumor necrosis factor-TNF; Tumor necrosis factor-α; HSP90; RIPK1; ferroptosis; CMA; necroptosis
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1819728116

Necroptosis and ferroptosis are two distinct necrotic cell death modalities with no known common molecular mechanisms. Necroptosis is activated by ligands of death receptors such as tumor necrosis factor-α (TNF-α) under caspase-deficient conditions, whereas ferroptosis is mediated by the accumulation of lipid peroxides upon the depletion/or inhibition of glutathione peroxidase 4 (GPX4). The molecular mechanism that mediates the execution of ferroptosis remains unclear. In this study, we identified 2-amino-5-chloro-N,3-dimethylbenzamide (CDDO), a compound known to inhibit heat shock protein 90 (HSP90), as an inhibitor of necroptosis that could also inhibit ferroptosis. We found that HSP90 defined a common regulatory nodal between necroptosis and ferroptosis. We showed that inhibition of HSP90 by CDDO blocked necroptosis by inhibiting the activation of RIPK1 kinase. Furthermore, we showed that the activation of ferroptosis by erastin increased the levels of lysosome-associated membrane protein 2a to promote chaperone-mediated autophagy (CMA), which, in turn, promoted the degradation of GPX4. Importantly, inhibition of CMA stabilized GPX4 and reduced ferroptosis. Our results suggest that activation of CMA is involved in the execution of ferroptosis.