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

Wafa B’Chir,Anne-Catherine Maurin,Laurent Parry,Alain Bruhat,Yuki Muranishi,Céline Jousse,Valérie Carraro,Georges Stepien,Pierre Fafournoux,Julien Averous

doi:10.1093/nar/gkt563

Wafa B’Chir, Anne-Catherine Maurin + Show 8 more

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https://doi.org/10.1093/nar/gkt563

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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.

Highlights

Mammalian cells have evolved complex signaling pathways that mediate the cellular response to stresses including UV irradiation, hypoxia, endoplasmic reticulum (ER) stress and deprivation of nutrients
In a preliminary experiment of amino acid-regulated gene screening, we reported that the expression of p62, an important marker of autophagy, was dramatically induced in response to amino acid starvation in mouse embryonic fibroblasts (MEFs) [39]. p62 known as sequestosome1/SQSTM1, is an autophagic adapter that acts as a cargo receptor for degradation of ubiquitinated substrates [38,40]. p62 possesses a short LC3-interacting region that facilitates direct interaction with MAP1LC3Band GABARAP-family members and causes p62 to be continuously and degraded by autophagy [41,42,43]
To determine whether genes involved in the autophagic process can be upregulated in response to amino acid starvation, the mRNA level of several genes encoding proteins involved in the formation, elongation and function of the autophagosome was measured

Summary

Introduction

Mammalian cells have evolved complex signaling pathways that mediate the cellular response to stresses including UV irradiation, hypoxia, endoplasmic reticulum (ER) stress and deprivation of nutrients. These pathways initiate a wide array of adaptative mechanisms and if necessary, programmed cell death [1,2]. The phosphorylation of eIF2a decreases translation of most mRNAs by inhibiting delivery of the initiator Met-tRNAi to the initiation complex. It favors increased translation of a selected number of mRNAs containing short upstream open reading frames [8]. ATF4 is a master regulator that plays a crucial role in the adaptation to stresses by regulating the transcription of many genes [3,10,11,12]

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