Activating transcription factor 4 and CCAAT/enhancer-binding protein-beta negatively regulate the mammalian target of rapamycin via Redd1 expression in response to oxidative and endoplasmic reticulum stress

Abstract

Regulation of mRNA translation in mammalian cells involves the coordinated control of mammalian target of rapamycin (mTOR) signaling. At present, limited information is available on the potential relevance of mTOR regulation, although translation inhibition during oxidative and endoplasmic reticulum (ER) stress is clearly important. In this study, we show that activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-beta (C/EBP-beta) negatively regulate mTOR via Redd1 expression in response to oxidative and ER stress. Oxidative and ER stress conditions induce rapid and significant activation of ATF4 downstream of eIF2 alpha phosphorylation, which is responsible for Redd1 expression. In our experiment, overexpression of ATF4 was associated with reduced mTOR activity via Redd1 expression, whereas suppression of ATF4 levels with small interfering RNA led to the recovery of decreased mTOR activity mediated by downregulation of Redd1 during oxidative and ER stress. We additionally identified Redd1 as a downstream effector of C/EBP-beta stimulated by ATF4 activated under the stress conditions examined. RNA interference studies provided further evidence of the requirement of C/EBP-beta for Redd1 expression. We conclude that the Redd1 gene is transactivated by the ATF4 and C/EBP family of transcription factors, leading to mTOR inhibition in response to oxidative and ER stress.