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

ABSTRACT: 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 hetero

SUBMITTER: Erb AL 

PROVIDER: S-EPMC12860950 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature