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

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

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Title: A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity
Author: Qiao, Shuxi; Dennis, Michael; Song, Xiufeng; Vadysirisack, Douangsone D.; Salunke, Devika; Nash, Zachary; Yang, Zhifen; Liesa, Marc; Yoshioka, Jun; Matsuzawa, Shu-Ichi; Shirihai, Orian S.; Lee, Richard T.; Reed, John C.; Ellisen, Leif W.

Note: Order does not necessarily reflect citation order of authors.

Citation: Qiao, S., M. Dennis, X. Song, D. D. Vadysirisack, D. Salunke, Z. Nash, Z. Yang, et al. 2015. “A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity.” Nature Communications 6 (1): 7014. doi:10.1038/ncomms8014. http://dx.doi.org/10.1038/ncomms8014.
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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.
Published Version: doi:10.1038/ncomms8014
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4421852/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:16120845
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