1. Academic Validation
  2. Chaperone-mediated autophagy is involved in the execution of ferroptosis

Chaperone-mediated autophagy is involved in the execution of ferroptosis

  • Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):2996-3005. doi: 10.1073/pnas.1819728116.
Zheming Wu 1 2 Yang Geng 1 Xiaojuan Lu 1 Yuying Shi 1 Guowei Wu 1 2 Mengmeng Zhang 1 Bing Shan 1 Heling Pan 3 Junying Yuan 4
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201203 Shanghai, China.
  • 2 University of Chinese Academy of Sciences, 100049 Beijing, China.
  • 3 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201203 Shanghai, China; panheling@sioc.ac.cn junying_yuan@hms.harvard.edu.
  • 4 Department of Cell Biology, Harvard Medical School, Boston, MA 02115 panheling@sioc.ac.cn junying_yuan@hms.harvard.edu.
Abstract

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.

Keywords

CMA; HSP90; RIPK1; ferroptosis; necroptosis.

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