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The integrated stress response and its role in cognition

CryoEM density for eIF2B(αβγδε)2, colored in distinct shades for each subunit. Density assigned to ISRIB
depicted in CPK coloring (oxygens highlighted in red, nitrogens in blue and chlorines in green)
and artistically contrasted from its target protein.

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 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. Phosphorylated eIF2 in turn inhibits eIF2B and arrests translation to mitigate stress.

We discovered a small molecule called ISRIB (integrated stress response inhibitor) that restores translation during stress by activating eIF2B. Remarkably, ISRIB enhances cognition and reverses cognitive deficits following brain injury in rodents. These effects highlight the potential of targeting the ISR for therapeutics. Recent work in the lab has determined the structure of eIF2B bound to ISRIB and a mechanism of action for the molecule. Future studies will focus on the critical regulation of this major translational control point.

ISR sensors detect and respond to a variety of cellular stresses such as unfolded proteins in the ER, viral infection, heme deficiency, and amino acid starvation. The four ISR sensors (PERK, PKR, HRI, and GCN2) are eIF2a kinases that become activated in response to cellular stress and result in phosphorylation of eIF2a. This phosphorylated form of eIF2a (eIF2a-P) inhibits the eIF2B-catalyzed guanine nucleotide exchange reaction of eIF2 and results in both the attenuation of global protein synthesis and de-repression of ATF4 mRNA translation.

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