Cells maintain their proteins in a functional and balanced state by regulating protein synthesis, folding, trafficking and degradation. A central regulatory target in this process is the nucleotide exchange factor eIF2B. Under favorable conditions eIF2B acts as a biological catalyst, efficiently unloading GDP from the translation initiation factor 2 (eIF2), a GTPase that is required for protein synthesis. Under conditions of stress, such as UPR activation, viral infection, or starvation, a conserved signaling network known as the integrated stress response (ISR) couples stress detection to the phosphorylation of eIF2. This phosphorylation event renders eIF2 from substrate for nucleotide exchange into a potent inhibitor of eIF2B to restrict protein synthesis. Relieved of a heavy translational burden, cells are afforded more time and resources to cope with stress.
Recently, we discovered a small molecule called ISRIB (integrated stress response inhibitor), and found it to activate eIF2B. Remarkably, when systemically administered to mice, ISRIB enhances cognition, confers neuroprotection, and reduces inflammation. These cytoprotective effects highlight the importance of eIF2B in human health and the potential that this pathway offers for therapeutic intervention. Furthermore, these findings suggest that eIF2B is not simply an on/off switch controlled by the ISR, but a finely tunable switch, much like a rheostat, that organizes complex processes such as memory and immunity. To make the most of these discoveries, a greater understanding of eIF2B regulatory control is needed. Specifically, we would like to know how ISRIB alters eIF2B structure to enhance nucleotide exchange, and whether cells can inherently capitalize on this type of regulation. Using this information we can more completely characterize the process of translation and precisely identify targets for the rational design of therapeutics.