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

Anthony L Erb1, Sara K Young-Baird2

  • 1Department of Biochemistry and Molecular Biology, Uniformed Services University, Bethesda, Maryland, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland, USA.

The Journal of Biological Chemistry
|December 29, 2025
PubMed

Insights

The Integrated Stress Response (ISR) impacts translation, but CDC123, a chaperone aiding eIF2 biogenesis, is a novel ISR regulator. Impaired CDC123 activity affects eIF2 assembly and translation, suggesting CDC123 as a therapeutic target for ISR-related diseases.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • The Integrated Stress Response (ISR) is crucial for cellular homeostasis, regulating global and mRNA-specific translation.
  • Dysregulation of the ISR is implicated in various disease states.
  • Stress-sensing kinases modulate translation by controlling the activity of the eukaryotic translation initiation factor 2 (eIF2) complex.

Purpose of the Study:

  • To identify novel regulators of the Integrated Stress Response (ISR).
  • To investigate the role of the chaperone CDC123 in eIF2 biogenesis and ISR modulation.
  • To explore CDC123 as a potential therapeutic target for ISR-related diseases.

Main Methods:

  • Investigated the role of CDC123 in eIF2 complex assembly and function.
  • Utilized genetic and pharmacological strategies to modulate CDC123 activity.
  • Examined the impact of impaired CDC123 on translational control and cellular outcomes during ISR activation.
  • Studied the mechanism of CDC123-mediated eIF2 assembly, including potential regulation by ATP hydrolysis.

Main Results:

  • Identified CDC123 as a novel regulator of the ISR, promoting eIF2 biogenesis.
  • Demonstrated that impaired CDC123 activity disrupts eIF2 complex assembly, leading to ISR-related translational defects via a noncanonical pathway.
  • Showed that pharmacological or genetic interventions can rescue these translational defects.
  • Provided evidence that CDC123-mediated eIF2 assembly may be regulated by ATP hydrolysis.

Conclusions:

  • CDC123 plays an essential role in eIF2 biogenesis and mRNA translation regulation.
  • CDC123 represents a potential therapeutic target for diseases associated with ISR dysregulation.
  • Elucidated novel mechanistic insights into eIF2 heterotrimer formation and its regulation.
Keywords:
cellular stressintegrated stress responseprotein synthesistranslation controltranslation initiation

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