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

Nat Commun. 2015 Apr 28;6:7014. doi: 10.1038/ncomms8014.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Autophagy-Related Proteins
  • Carrier Proteins / metabolism*
  • Cysteine Endopeptidases / metabolism*
  • Energy Metabolism
  • Exercise Tolerance
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Oxidative Stress
  • Reactive Oxygen Species / metabolism*
  • Thioredoxins / metabolism*
  • Transcription Factors / metabolism*


  • Autophagy-Related Proteins
  • Carrier Proteins
  • Ddit4 protein, mouse
  • Reactive Oxygen Species
  • Transcription Factors
  • Txnip protein, mouse
  • Thioredoxins
  • Atg4b protein, mouse
  • Cysteine Endopeptidases