Abstract: Maintenance of protein homeostasis or “proteostasis” is essential for the functioning and viability of cells. This is in particular the case for cells like neurons that cannot self-renew and acquire unique functional properties during their lifetime. Cellular proteostatic stress responses are in place to protect cells from damage in case of proteostatic challenges. The integrated stress response (ISR) is one of the key proteostatic stress responses in the cell (Costa-Mattioli and Walter, 2020). The ISR is the downstream convergence point for the four stress-induced eIF2α kinases (EIF2AK1–4) that control stress-regulated protein translation via phosphorylation of the translation factor eIF2α. ISR activation results in a transient reduction of global translation while it concomitantly enhances the translation of specific mRNAs, including that encoding the activating transcription factor 4 (ATF4). Together, the translational control mediated by the ISR results in a temporary reduction of the overall protein load and the selectively increased expression of proteins that contribute to restoration of the proteostatic balance.