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Basal level of ATF4 promotes T cell readiness for activation-induced proliferation [RNA-seq]

ABSTRACT: Stress responding elements such as eIF2α phosphorylation are either upregulated or required during late-phase T cell activation and differentiation. However, it is not well understood whether these elements are essential within the first 12-24 hours post-stimulation, a period when mitochondrial activation and metabolic reprogramming are critical. Here, we demonstrate that T cell activation-induced mTOR and GCN2 phosphorylation leads to the upregulation of ATF4 protein as early as 12 hours after stimulation. This early induction of ATF4 has transcriptional activities that positively or negatively regulate stress response, signaling, and metabolism. Loss of Atf4 in T cells alters transcriptome dynamics, impairs amino acid transport and biosynthesis, and disrupts cellular adaptive responses to ER stress and oxidative stress. It also hinders cell growth, resulting in defective effector cell differentiation in vitro or in vivo in a chronic LCMV infection model. Our findings suggest that a basal level of ATF4 during the early phase of T cell activation enhances the preparedness of cells to cope with integrated nutritional, protein folding, and oxidative stresses during the activation course. This, in turn, protects cells from stress-related cell death or senescence.

ORGANISM(S): Mus musculus

PROVIDER: GSE288143 | GEO | 2026/01/21

REPOSITORIES: GEO

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Project description:Disruptions of protein homeostasis in the endoplasmic reticulum (ER) elicit activation of the unfolded protein response (UPR), a translation- and transcription-coupled proteostatic stress response pathway. The primary translational control arm of the UPR is initiated by the PERK-dependent phosphorylation of eIF2Î±, leading to a large-scale reprogramming of translation and subsequent activation of an ATF4-mediated transcriptional program. It has remained challenging, however, to accurately evaluate the contribution of each component of the eIF2Î±/ATF4 pathway to the remodelling of transcription and translation. Here, we have used mouse embryonic fibroblasts containing either a knock-in of the non-phosphorylatable eIF2Î± S51A mutant or knock-out for ATF4 by ribosome profiling and mRNA-seq to define the specific contributions of eIF2Î± phosphoryation and ATF4 in controlling the translational and transcriptional components of the UPR. These studies show that the transcriptional and translational targets of each P-eIF2Î±, ATF4, and the other UPR gene expression programs overlapped extensively, leading to a core set of UPR genes whose robust expression in response to ER stress is driven by multiple mechanisms. The identification of other, more factor-specific targets illustrated the potential for functional specialization of the UPR. As the UPR progressed temporally, cells employed distinct combinations of transcriptional and translational mechanisms, initiated by different factors, to adapt to ongoing stress. These effects were accompanied by a buffering effect where changes in mRNA levels were coupled to opposing changes in ribosome loading, a property which makes cooperation between transcription and translation essential to confer robust protein expression. Translational analysis by ribosome profiling and mRNA-seq of PERK pathways mutants during the UPR. Mouse embryonic fibroblasts (MEFs) lacking components of the PERK pathway (eIF2a phosphorylation and ATF4) were subjected to ER stress and analyzed by ribosome profiling.

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Basal level of ATF4 promotes T cell readiness for activation-induced proliferation [RNA-seq]

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