A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity

Shuxi Qiao, Michael Dennis, Xiufeng Song, Douangsone D. Vadysirisack, Devika Salunke, Zachary Nash, Zhifen Yang, Marc Liesa, Jun Yoshioka, Shu Ichi Matsuzawa, Orian S. Shirihai, Richard T. Lee, John C. Reed, Leif W. Ellisen

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

Macroautophagy (autophagy) is a critical cellular stress response; however, the signal transduction pathways controlling autophagy induction in response to stress are poorly understood. Here we reveal a new mechanism of autophagy control whose deregulation disrupts mitochondrial integrity and energy homeostasis in vivo. Stress conditions including hypoxia and exercise induce reactive oxygen species (ROS) through upregulation of a protein complex involving REDD1, an mTORC1 inhibitor and the pro-oxidant protein TXNIP. Decreased ROS in cells and tissues lacking either REDD1 or TXNIP increases catalytic activity of the redox-sensitive ATG4B cysteine endopeptidase, leading to enhanced LC3B delipidation and failed autophagy. Conversely, REDD1/TXNIP complex expression is sufficient to induce ROS, suppress ATG4B activity and activate autophagy. In Redd1-/- mice, deregulated ATG4B activity and disabled autophagic flux cause accumulation of defective mitochondria, leading to impaired oxidative phosphorylation, muscle ATP depletion and poor exercise capacity. Thus, ROS regulation through REDD1/TXNIP is physiological rheostat controlling stress-induced autophagy.

Original languageEnglish
Article number7014
JournalNature Communications
Volume6
DOIs
StatePublished - 28 Apr 2015

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