A REDD1/TXNIP pro-oxidant complex regulates ATG4B activity to control stress-induced autophagy and sustain exercise capacity.
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.
1] Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA.
Shuxi
S
Qiao
Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
Michael
M
Dennis
1] Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA.
Xiufeng
X
Song
1] Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA.
Douangsone D
DD
Vadysirisack
Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
Devika
D
Salunke
Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
Zachary
Z
Nash
Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Zhifen
Z
Yang
Department of Medicine, Evans Center, Mitochondria ARC, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Marc
M
Liesa
1] Harvard Medical School, Boston, Massachusetts 02115, USA [2] Regenerative Medicine Center, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Jun
J
Yoshioka
Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Shu-Ichi
S
Matsuzawa
1] Department of Medicine, Evans Center, Mitochondria ARC, Boston University School of Medicine, Boston, Massachusetts 02118, USA [2] Department of Clinical Biochemistry, Faculty of Medicine, Ben Gurion University of the Negev, Beer-Sheva 8410501, Israel.
Orian S
OS
Shirihai
1] Harvard Medical School, Boston, Massachusetts 02115, USA [2] Regenerative Medicine Center, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Richard T
RT
Lee
1] Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA [2] Roche Pharmaceutical Research and Early Development, Basel 4070, Switzerland.
John C
JC
Reed
1] Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA.
Leif W
LW
Ellisen
D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004734:Energy Metabolism; D017079:Exercise Tolerance; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; C469992:Ddit4 protein, mouse; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C445672:Txnip protein, mouse; D013879:Thioredoxins; C582881:Atg4b protein, mouse; D003546:Cysteine Endopeptidases