13 eIF2α Phosphorylation in Cellular Stress Responses and Disease

Phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) is a highly conserved regulatory event activated in response to diverse stresses (Chapter 12). It elicits translational reprogramming as its primary consequence and secondarily affects the transcriptional profile of cells (Chapter 9). Together, these two strands of the eIF2α phosphorylation-dependent integrated stress response (ISR) broadly affect gene expression, amino acid and energy metabolism, and the protein-folding environment in the cell. Rare human mutations and transgenic mice, in which components of the ISR have been severely altered, reveal the pathway’s importance to mammalian pathophysiology. Here, we review the components of the mammalian ISR and consider their function in the context of the cellular adaptation to protein mis-folding, nutrient deprivation, and other stresses. We address the potential importance of the ISR to such common human diseases as diabetes mellitus, the metabolic syndrome, osteoporosis, neurodegeneration, and demyelination. Special emphasis is placed on instances suggesting that failure of homeostasis in the ISR contributes to disease, and these are considered in the context of the hypothetical therapeutic opportunities they present. BACKGROUND Molecular and Physiological Principles That Determine the Consequences of eIF2α Phosphorylation Phosphorylation on serine 51 of its α subunit converts eIF2 from a substrate to an inhibitor of its guanine nucleotide exchange factor, eIF2B. Thus, the level of phosphorylated eIF2α regulates the rate at which eIF2 can be recycled to the GTP-bound form to join in a ternary complex with charged initiator methionyl-tRNA and promote the initiation of mRNA translation (Chapter 4).