Abstract
Cells are continuously exposed to physiological and environmental stressors that disrupt homeostasis, triggering adaptive mechanisms such as the integrated stress response (ISR). A central feature of ISR is the selective translation of activating transcription factor 4 (ATF4), which orchestrates gene programs essential for metabolic adaptation and survival. Stress-induced acute ATF4 expression occurs in diverse mammalian cell types and is typically protective; however, chronic activation contributes to pathologies including cancer and neurodegeneration. Canonical ISR (c-ISR) is initiated by phosphorylation of eIF2α in response to stressors such as endoplasmic reticulum or mitochondrial dysfunction, hypoxia, nutrient deprivation, and infections. This modification suppresses global protein synthesis while promoting ATF4 translation through upstream open reading frames (uORFs) in its 5'UTR. Recently, an alternative pathway, split ISR (s-ISR), enabling ATF4 translation independently of eIF2α phosphorylation, was identified in mice, suggesting ISR adaptability, though its relevance in humans remains unclear. Under normal conditions, cap-dependent translation predominates, mediated by the eIF4F complex and requiring the activity of eIF2B at its initial steps. During translational stress, eIF2α phosphorylation inhibits eIF2B activity, resulting in the formation of stalled initiation complexes, which can aggregate into stress granules (SGs). SGs sequester mRNAs and translation initiation factors, further repressing global translation, while ATF4 mRNA largely escapes sequestration, enabling selective translation. This partitioning highlights a finely tuned regulatory mechanism balancing ATF4 expression during stress. Recent advances reveal that, beyond cis-regulatory uORFs, trans-acting factors such as translation initiation factors and associated RNA-binding proteins critically influence ATF4 translation. Understanding these mechanisms provides insight into ISR plasticity and its implications for development, aging, and disease.