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Review
. 2023 Feb 7:16:1112253.
doi: 10.3389/fnmol.2023.1112253. eCollection 2023.

A stay of execution: ATF4 regulation and potential outcomes for the integrated stress response

Graham Neill  1 , Glenn R Masson  1
Affiliations
Review

A stay of execution: ATF4 regulation and potential outcomes for the integrated stress response

Graham Neill et al. Front Mol Neurosci. .

Abstract

ATF4 is a cellular stress induced bZIP transcription factor that is a hallmark effector of the integrated stress response. The integrated stress response is triggered by phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 complex that can be carried out by the cellular stress responsive kinases; GCN2, PERK, PKR, and HRI. eIF2α phosphorylation downregulates mRNA translation initiation en masse, however ATF4 translation is upregulated. The integrated stress response can output two contradicting outcomes in cells; pro-survival or apoptosis. The mechanism for choice between these outcomes is unknown, however combinations of ATF4 heterodimerisation partners and post-translational modifications have been linked to this regulation. This semi-systematic review article covers ATF4 target genes, heterodimerisation partners and post-translational modifications. Together, this review aims to be a useful resource to elucidate the mechanisms controlling the effects of the integrated stress response. Additional putative roles of the ATF4 protein in cell division and synaptic plasticity are outlined.

Keywords: ATF4; ISR; PTM; apoptosis; cell division; dimerization; synaptic plasticity; target genes.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The integrated stress response and regulation of eIF2α. The eIF2 kinases GCN2, PERK, PKR and HRI phosphorylate eIF2α at serine 51 in response to a range of stress stimuli. DNAJC3 (also known as P58IPK) is known to inhibit the activity of GCN2, PERK and PKR (Roobol et al., 2015). Protein phosphatase 1 regulatory subunit 15A (PPP1R15A) and PPP1R15B are eIF2 adapters for the phosphatase catalytic subunit, PPP1CC, which downregulate the ISR via dephosphorylation of eIF2α at serine 51. PPP1R15B is constitutively expressed whereas PPP1R15A is induced by the integrated stress response in a negative feedback mechanism (Novoa et al., 2001; Brush et al., 2003; Jousse et al., 2003; Kojima et al., 2003). Phosphorylation of eIF2α causes eIF2 to inhibit eIF2B from acting as a guanine nucleotide exchange factor for eIF2 and the initiator Met-tRNAi cannot bind eIF2 unless GTP is present. Ultimately, eIF2α phosphorylation inhibits eIF2 ternary complex formation and therefore inhibits translation initiation leading to upregulation of ATF4.
Figure 2
Figure 2
Selection process to identify relevant ATF4-interactors, PTMs and target-genes. For interactions studies, a total of 171 studies were investigated in addition to 93 interactions listed on the IntAct database, this was screened to identify an additional 65 unique interaction partners. After removal of interactions with non-direct evidence and those found only in a single publication, 14 proteins were identified. For PTMs, PhosphositePlus (PSP), Uniprot and Biogrid were all screened for PTMs. After checking for duplicates, 44 hits remained. Removal of predicted, i.e., as of yet observed PTMs in human, resulted in 33 PTMS. For target genes, 145 relevant articles were found from literature database searches, and after application of inclusion criteria, a total of 234 possible gene targets were identified. After stringency criteria were applied, a total of 41 hits were included.
Figure 3
Figure 3
Post-translational Modifications of Human ATF4.
See this image and copyright information in PMC

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