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 and Leif W. Ellisen ()
Additional contact information
Shuxi Qiao: Massachusetts General Hospital Cancer Center
Michael Dennis: Massachusetts General Hospital Cancer Center
Xiufeng Song: Massachusetts General Hospital Cancer Center
Douangsone D. Vadysirisack: Massachusetts General Hospital Cancer Center
Devika Salunke: Massachusetts General Hospital Cancer Center
Zachary Nash: Massachusetts General Hospital Cancer Center
Zhifen Yang: Sanford-Burnham Medical Research Institute
Marc Liesa: Evans Center, Mitochondria ARC, Boston University School of Medicine
Jun Yoshioka: Harvard Medical School
Shu-Ichi Matsuzawa: Sanford-Burnham Medical Research Institute
Orian S. Shirihai: Evans Center, Mitochondria ARC, Boston University School of Medicine
Richard T. Lee: Harvard Medical School
John C. Reed: Sanford-Burnham Medical Research Institute
Leif W. Ellisen: Massachusetts General Hospital Cancer Center

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8014

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