| First Author | Qiao S | Year | 2015 |
| Journal | Nat Commun | Volume | 6 |
| Pages | 7014 | PubMed ID | 25916556 |
| Mgi Jnum | J:222791 | Mgi Id | MGI:5645606 |
| Doi | 10.1038/ncomms8014 | Citation | Qiao S, et al. (2015) A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity. Nat Commun 6:7014 |
| abstractText | 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. |
