title: mTORC1 dependent regulation of REDD1 protein stability.
abstract: REDD1 is known to be transcriptionally upregulated in hypoxia. During hypoxic stress, REDD1 plays an important role as a mediator of mTORC1 inhibition. REDD1 is also subject to highly dynamic transcriptional regulation in response to a variety of other stress signals. In addition, the REDD1 protein is highly unstable. However, it is currently not well understood how REDD1 protein stability is regulated. In this study, we discovered that mTORC1 regulates REDD1 protein stability in a 26S proteasome dependent manner. Inhibition of mTORC1 resulted in reduced REDD1 protein stability and a consequent decrease in REDD1 expression. Conversely, activation of the mTORC1 pathway increases REDD1 protein levels. We show that REDD1 degradation is not regulated by HUWE1, Cul4a or other Cullin E3 ubiquitin ligases. Our study shows that mTORC1 increases REDD1 protein stability and reveals a novel mTORC1-REDD1 feedback loop. This feedback mechanism may limit the inhibitory action of REDD1 on mTORC1.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Chia Yee
authors.initials: CY
authors.lastname: Tan
authors.forename: Thilo
authors.initials: T
authors.lastname: Hagen
mesh_terms: D002460:Cell Line; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: C114234:CUL4A protein, human; D044842:Cullin Proteins; C469991:DDIT4 protein, human; D046912:Multiprotein Complexes; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases; D000071679:Glycogen Synthase Kinase 3 beta; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease