ATF4: Orchestrating Cellular Stress Adaptation, Metabolism, and Immune Regulation in Health and Disease

Activating transcription factor 4 (ATF4) is a master transcription factor of integrated stress response (ISR), an evolutionarily conserved intracellular signaling network that helps the cell, tissue, and organism to adapt to various unpredictable environmental fluctuations, mitigate the challenges, and maintain health. Stress-induced ATF4 expression regulates a wild variety of gene expression programs to enable stress management and repair for cell homeostasis and integrity. However, chronic ATF4 activation contributes to pathologies including cancer, inflammation, and neurodegeneration. Extensive studies have revealed that ATF4 regulates many cellular processes including autophagy, apoptosis, metabolism, and inflammation. Emerging evidence has uncovered new signaling pathways in regulation of ATF4 expression and activation, including at transcriptional, translational, and post-translational levels, and new functions of ATF4 in the progression of various metabolic and stress-related diseases, including inflammation, cancer, and cardiovascular disease. The diversity of ATF4 functions is increasingly appreciated. This review summarizes the recent findings of the complex regulatory network of ATF4 activity and its roles in integrating stress responses, metabolic reprogramming, unfolded protein responses, autophagy, inflammation, and immunity.