REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A-DDB1 ubiquitin ligase.
The cellular response to hypoxia involves several signalling pathways that mediate adaptation and survival. REDD1 (regulated in development and DNA damage responses 1), a hypoxia-inducible factor-1 target gene, has a crucial role in inhibiting mammalian target of rapamycin complex 1 (mTORC1) signalling during hypoxic stress. However, little is known about the signalling pathways and post-translational modifications that regulate REDD1 function. Here, we show that REDD1 is subject to ubiquitin-mediated degradation mediated by the CUL4A-DDB1-ROC1-beta-TRCP E3 ligase complex and through the activity of glycogen synthase kinase 3beta. Furthermore, REDD1 degradation is crucially required for the restoration of mTOR signalling as cells recover from hypoxic stress. Our findings define a mechanism underlying REDD1 degradation and its importance for regulating mTOR signalling.
Katiyar
Samiksha
S
Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Liu
Enbo
E
Knutzen
Christine A
CA
Lang
Elizabeth S
ES
Lombardo
Christian R
CR
Sankar
Sabita
S
Toth
Julia I
JI
Petroski
Matthew D
MD
Ronai
Ze'ev
Z
Chiang
Gary G
GG
D002352:Carrier Proteins / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015151:Immunoblotting; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D055550:Protein Stability; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
C114234:CUL4A protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C091435:DDB1 protein, human; C469991:DDIT4 protein, human; D004268:DNA-Binding Proteins; D011500:Protein Synthesis Inhibitors; C479529:RBX1 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors; D044844:beta-Transducin Repeat-Containing Proteins; D003513:Cycloheximide; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C546842:MTOR protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3