RT Journal Article
SR Electronic
T1 Clockophagy is a novel selective autophagy process favoring ferroptosis
JF Science Advances
JO Sci Adv
FD American Association for the Advancement of Science
SP eaaw2238
DO 10.1126/sciadv.aaw2238
VO 5
IS 7
A1 Yang, Minghua
A1 Chen, Pan
A1 Liu, Jiao
A1 Zhu, Shan
A1 Kroemer, Guido
A1 Klionsky, Daniel J.
A1 Lotze, Michael T.
A1 Zeh, Herbert J.
A1 Kang, Rui
A1 Tang, Daolin
YR 2019
UL http://advances.sciencemag.org/content/5/7/eaaw2238.abstract
AB 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.