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FOXO1 controls protein synthesis and transcript abundance of mutant polyglutamine proteins, preventing protein

Gabriel Vasata Furtado1, Jing Yang1, Di Wu1

  • 1Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands.

Human Molecular Genetics
|April 6, 2021
PubMed

Insights

Forkhead box protein 1 (FOXO1) prevents toxic protein aggregation in CAG-repeat diseases by reducing pathogenic RNA and protein synthesis. This mechanism is independent of autophagy and the ubiquitin-proteasome system.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Forkhead box protein 1 (FOXO1) is a transcription factor involved in protein homeostasis.
  • Elevated FOXO orthologs can prevent polyglutamine (polyQ) protein aggregation in CAG-repeat diseases.
  • The precise role of FOXO1 in targeting mutant proteins for degradation remains unclear.

Purpose of the Study:

  • To investigate the role of FOXO1 in preventing toxic polyglutamine aggregation in human cells.
  • To elucidate the mechanism by which FOXO1 affects polyQ aggregation.
  • To determine if FOXO1's effect is mediated by autophagy or the ubiquitin-proteasome system.

Main Methods:

  • Cellular models of CAG-repeat diseases.
  • Manipulation of FOXO1 expression levels.
  • Assessment of polyQ aggregation.
  • Analysis of autophagy and ubiquitin-proteasome system activity.
  • RNA immunoprecipitation and protein binding assays.

Main Results:

  • Increased FOXO1 expression prevents toxic polyQ aggregation; reduced FOXO1 accelerates it.
  • FOXO1's effect on polyQ aggregation is independent of autophagy and UPS-mediated degradation.
  • FOXO1 specifically downregulates protein synthesis from expanded CAG repeat transcripts.
  • FOXO1 recruits IGF2BP3 to pathogenic CAG transcripts, decreasing their levels and reducing amyloidogenesis.

Conclusions:

  • FOXO1 preserves protein homeostasis by downregulating synthesis of toxic proteins from expanded CAG repeat transcripts.
  • FOXO1 reduces aberrant RNA species accumulation, mitigating toxicity in CAG-repeat diseases.
  • FOXO1 represents a novel therapeutic target for managing CAG-repeat disorders.

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