The eIF2α/ATF4 pathway is essential for stress-induced autophagy gene expression

TLDR

eIF2α phosphorylation during stress suppresses global translation while selectively translating ATF4, a master regulator of adaptive gene transcription. GCN2 and PERK kinases, together with ATF4 and CHOP transcription factors, drive transcription of genes involved in autophagosome formation, elongation, and function. The study shows that the eIF2α/ATF4 pathway orchestrates an autophagy gene transcription program, classifies genes by ATF4/CHOP dependence, and that varying CHOP/ATF4 promoter binding patterns fine‑tune the response to stress intensity.

Abstract

In response to different environmental stresses, eIF2α phosphorylation represses global translation coincident with preferential translation of ATF4, a master regulator controlling the transcription of key genes essential for adaptative functions. Here, we establish that the eIF2α/ATF4 pathway directs an autophagy gene transcriptional program in response to amino acid starvation or endoplasmic reticulum stress. The eIF2α-kinases GCN2 and PERK and the transcription factors ATF4 and CHOP are also required to increase the transcription of a set of genes implicated in the formation, elongation and function of the autophagosome. We also identify three classes of autophagy genes according to their dependence on ATF4 and CHOP and the binding of these factors to specific promoter cis elements. Furthermore, different combinations of CHOP and ATF4 bindings to target promoters allow the trigger of a differential transcriptional response according to the stress intensity. Overall, this study reveals a novel regulatory role of the eIF2α–ATF4 pathway in the fine-tuning of the autophagy gene transcription program in response to stresses.