CDC123 is an ATPase that modulates mRNA translation and the integrated stress response by regulating eIF2 complex assembly.

Hyperactivation and hypoactivation of the integrated stress response (ISR) results in impaired regulation of global and mRNA-specific translation in multiple disease contexts. During the ISR, specific stress-sensing kinases modulate translation by regulating the activity of the heterotrimeric eukaryotic translation initiation factor eIF2. Here, we identify the chaperone CDC123, which promotes eIF2 biogenesis, as a novel regulator of the ISR. We find that impaired CDC123 activity reduces eIF2 complex assembly, promoting the translational and cellular outcomes of the ISR through a noncanonical mechanism. Pharmacological or genetic strategies are sufficient to rescue the translational defects associated with impaired CDC123 activity. In addition, we report functional insights into eIF2 heterotrimer formation and provide the first evidence that CDC123-mediated eIF2 complex assembly may be regulated by ATP hydrolysis. These data emphasize the essential contribution of eIF2 biogenesis in mRNA translation regulation, and highlight CDC123 as a possible therapeutic target in the treatment of ISR-related diseases.