ATF4

Activating transcription factor 4 (ATF4) is a basic leucine zipper transcription factor of the ATF/CREB family that regulates gene expression in response to cellular stress. In mammals, ATF4 is a key effector of the integrated stress response (ISR), coordinating adaptive programs during amino acid deprivation, oxidative stress, ER stress, and other insults.

ATF4 expression is controlled at the level of translation. Stress-activated kinases such as PERK, GCN2, and PKR phosphorylate eIF2α, reducing global translation but enabling selective translation of ATF4 due to two upstream open reading frames in its 5' untranslated region. Accumulated ATF4 then binds to CRE/CARE elements and induces a transcriptional program.

Key ATF4 targets include amino acid metabolism and transport genes (e.g., ASNS, SLC7A11), antioxidant and redox genes (e.g., GCLC, GSS), and autophagy-related genes. ATF4 also induces CHOP (DDIT3) during prolonged stress, linking ISR to apoptosis in some contexts. The balance of adaptive versus pro-apoptotic outcomes depends on the duration and context of activation.

Structurally, ATF4 contains a basic region-leucine zipper for DNA binding and dimerization with other bZIP proteins; it can form homodimers or heterodimers with members of the C/EBP and CREB families to regulate target promoters.

ATF4 signaling has been implicated in various diseases, including cancer, neurodegenerative disorders, and metabolic disease, where it modulates cell survival, metabolism, and redox homeostasis. Its activity is a potential target for therapeutic intervention in contexts of chronic stress.