Clockophagy is a novel selective autophagy process favoring ferroptosis

• Published in: Science advances Vol. 5; no. 7; p. eaaw2238
• Main Authors: Yang, Minghua, Chen, Pan, Liu, Jiao, Zhu, Shan, Kroemer, Guido, Klionsky, Daniel J., Lotze, Michael T., Zeh, Herbert J., Kang, Rui, Tang, Daolin
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.07.2019
• Subjects: Animals; Apoptosis - genetics; ARNTL Transcription Factors - genetics; Autophagy - genetics; Biological Clocks - genetics; Ferroptosis - genetics; Gene Expression Regulation, Neoplastic - genetics; Heterografts; HL-60 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor-Proline Dioxygenases - genetics; Iron - metabolism; Lipid Peroxidation - genetics; Lysosomes - genetics; Mice; Neoplasms - genetics; Neoplasms - pathology; Reactive Oxygen Species - metabolism; SciAdv r-articles; Sequestosome-1 Protein - genetics; Signal Transduction; Signal Transduction - genetics
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aaw2238

Autophagy-dependent cell death may hold the key to understanding the molecular basis of ferroptosis. 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.