eIF2B and the Integrated Stress Response: a structural and mechanistic view.

The eukaryotic translation initiation factor eIF2 is a GTPase, which brings the initiator Met-tRNAi to the ribosome as the eIF2-GTP*Met-tRNAi ternary complex (TC). TC regeneration is catalyzed by the guanine nucleotide exchange factor (GEF) eIF2B. eIF2 phosphorylation by several stress-induced kinases converts it into a competitive inhibitor of eIF2B. Inhibition of eIF2B activity lowers cellular TC concentrations, which in turn triggers the Integrated Stress Response (ISR). Depending on its degree of activation and duration, ISR protects the cell from the stress or can itself induce apoptosis. ISR dysregulation is a causative factor in the pathology of multiple neurodegenerative disorders, while ISR inhibitors are neuroprotective. The realization that eIF2B is a promising therapeutic target has triggered significant interest in its structure and the mechanisms of its action and regulation. Recently, four groups published the Cryo-EM structures of eIF2B with its substrate eIF2 and/or its inhibitor, phosphorylated eIF2 (eIF2(alpha-P)). While all three structures of the nonproductive eIF2B*eIF2(alpha-P) complex are similar to each other, there is a sharp disagreement between the published structures of the productive eIF2B*eIF2 complex: one group reports a structure similar to that of the nonproductive complex, whereas two others observe a vastly different eIF2B*eIF2 complex. Here, we discuss the recent reports on the structure, function, and regulation of eIF2B; the pre-clinical data on the use of ISR inhibitors for treatment of neurodegenerative disorders; and how the new structural and biochemical information can inform and influence the use of eIF2B as a therapeutic target.