SIRT1 Suppresses Activating Transcription Factor 4 (ATF4) Expression in Response to Proteasome Inhibition

Unfolded and misfolded proteins that are inappropriatelyprocessed in the endoplasmic reticulum (ER) are eliminatedvia proteasomal degradation. Attenuation or inhibition ofproteasomal degradation activity leads to the accumulationof abnormal proteins in the ER, thereby eliciting ER stress[6,17,19]. Activating transcription factor 4 (ATF4), a memberof the ATF/CREB (activating transcription factor/cyclicAMP response element binding protein) family, mediatesresponses to unfolded protein and ER stress [6]. The majority of normal cells exhibit not only inefficienttranslation of ATF4 mRNA but also active post-translationaldegradation of ATF4 protein [1]. Therefore, the basal levelof ATF4 protein in normal cells remains too low for detection,despite the ubiquitous expression of ATF4 mRNA [1]. Withthe development of stress conditions, such as deprivationof amino acids, glucose, or oxygen, cells respond byaccumulating ATF4 protein, mainly due to changes intranslation and post-translational degradation, and partlydue to transcription [2, 5, 11]. Under these stress conditions,translational inhibition of ATF4 mRNA by its upstreamopen reading frame is bypassed [1, 10] and degradation ofprotein by E3 ligase β-TRCP reduced [1], leading toaccumulation of ATF4 protein. ATF4 translation is basicallyregulated via phosphorylation of eIF2α [10]. Phosphorylationof eIF2α, induced during stress, preferentially increasesATF4 translation while suppressing that of most othermRNA molecules [11, 16, 24, 28]. Based on the type ofstress, different kinases are activated to trigger eIF2αphosphorylation, including PERK for endoplasmic reticulumstress, GCN2 for amino acid deprivation [26], PKR for viral