Transcriptional Repression of ATF4 Gene by CCAAT/Enhancer-binding Protein β (C/EBPβ) Differentially Regulates Integrated Stress Response

Abstract Different environmental stresses induce the phosphorylation of eIF2 (eIF2~P), repressing global protein synthesis coincident with preferential translation of ATF4. ATF4 is a transcriptional activator of genes involved in metabolism and nutrient uptake, anti-oxidation, and the regulation of apoptosis. Because ATF4 is a common downstream target that integrates signaling from different eIF2 kinases and their respective stress signals, the eIF2~P/ATF4 pathway is collectively referred to as the Integrated Stress Response (ISR). While eIF2~P elicits translational control in response to many different stresses, there are selected stresses, such as exposure to UV irradiation, which do not increase ATF4 expression despite robust eIF2~P. The rationale for this discordant induction of ATF4 expression and eIF2~P in response to UV irradiation is that transcription of ATF4 is repressed, and therefore ATF4 mRNA is not available for preferential translation. In this study, we show that C/EBPβ is a transcriptional repressor of ATF4 during UV stress. C/EBPβ binds to critical elements in the ATF4 promoter resulting in its transcriptional repression. Expression of C/EBPβ increases in response to UV stress, and the LIP isoform of C/EBPβ but not the LAP version, represses ATF4 transcription. Loss of the LIP isoform results in increased ATF4 mRNA levels in response to UV irradiation, and subsequent recovery of ATF4 translation, leading to enhanced expression of its target genes. Together these results illustrate how eIF2~P and translational control, combined with transcription factors regulated by alternative signaling pathways, can direct programs of gene expression that are specifically tailored to each environmental stress.