@article{6d2e0883377f4d83864029b6a8fb6cd8,
title = "Clockophagy is a novel selective autophagy process favoring ferroptosis",
abstract = "Ferroptosis is a form of nonapoptotic regulated cell death driven by iron-dependent lipid peroxidation. Autophagy involves a lysosomal degradation pathway that can either promote or impede cell death. A high level of autophagy has been associated with ferroptosis, but the mechanisms underpinning this relationship are largely elusive. We characterize the contribution of autophagy to ferroptosis in human cancer cell lines and mouse tumor models. We show that “clockophagy,” the selective degradation of the core circadian clock protein ARNTL by autophagy, is critical for ferroptosis. We identify SQSTM1 as a cargo receptor responsible for autophagic ARNTL degradation. ARNTL inhibits ferroptosis by repressing the transcription of Egln2, thus activating the prosurvival transcription factor HIF1A. Genetic or pharmacological interventions blocking ARNTL degradation or inhibiting EGLN2 activation diminished, whereas destabilizing HIF1A facilitated, ferroptotic tumor cell death. Thus, our findings reveal a new pathway, initiated by the autophagic removal of ARNTL, that facilitates ferroptosis induction.",
author = "Minghua Yang and Pan Chen and Jiao Liu and Shan Zhu and Guido Kroemer and Klionsky, {Daniel J.} and Lotze, {Michael T.} and Zeh, {Herbert J.} and Rui Kang and Daolin Tang",
note = "Funding Information: We thank D. Primm (Department of Surgery, University of Texas Southwestern Medical Center) for critical reading of the manuscript. We thank N. Yates (University of Pittsburgh) and X. Zeng (University of Pittsburgh) for help in the MS/MS assay (P30CA047904). We also thank S. Gygi (Department of Cell Biology, Harvard Medical School) for suggestion in the use of Dionex HPLC system. D.T. was supported by grants from the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD). R.K., D.J.K., and M.T.L. were supported by grants R01CA211070, GM131919, and R01CA181450 and R01CA206012, respectively, from the U.S. National Institutes of Health. J.L. was supported by grants from the National Natural Science Foundation of China (81830048, 81772508, and 31671435). M.Y. was supported by grants from the National Natural Science Foundation of China (81570154 and 81100359) and the Natural Science Foundation of Hunan Province (2016JJ3171). G.K. was supported by the Ligue contre le Cancer Comit{\'e} de Charente-Maritime ({\'e}quipe labellis{\'e}e), the Agence National de la Recherche (ANR)—Programme Blanc, the ANR under the frame of E-Rare-2 (the ERA-Net for Research on Rare Diseases), the Association pour la recherche sur le cancer (ARC), the Canc{\'e}rop{\^o}le Ile-de-France, the Chancellerie des universit{\'e}s de Paris (Legs Poix), the Fondation pour la Recherche M{\'e}dicale (FRM), the European Commission (ArtForce), the European Research Council (ERC), the Fondation Carrefour, the Institut National du Cancer (INCa), INSERM [Heterogeneity of Tumors & Ecosystem (HTE) Program], the Institut Universitaire de France, the Leducq Foundation, the LabEx Immuno-Oncology, the RHU Torino Lumi{\`e}re, the Seerave Foundation, the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), the SIRIC Cancer Research and Personalized Medicine (CARPEM), and the Paris Alliance of Cancer Research Institutes (PACRI). Publisher Copyright: Copyright {\textcopyright} 2019 The Authors.",
year = "2019",
month = jul,
day = "24",
doi = "10.1126/sciadv.aaw2238",
language = "English (US)",
volume = "5",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "7",
}