Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt

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Published on: August 23, 2024

Kazuyuki Yamagata1, Hiroaki Daitoku, Yuta Takahashi

  • 1Center for Tsukuba Advanced Research Alliance, Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.

Molecular Cell
|October 28, 2008
PubMed

Insights

Protein arginine methyltransferase 1 (PRMT1) regulates Forkhead box O1 (FOXO1) stability by blocking Akt phosphorylation. This methylation prevents FOXO1 degradation, impacting cell survival and apoptosis.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Epigenetics

Background:

  • Forkhead box O (FOXO) transcription factors are crucial for cell survival.
  • FOXO activity is negatively regulated by the PI3K-Akt signaling pathway.
  • Akt-mediated phosphorylation targets FOXO for cytoplasmic localization and proteasomal degradation.

Purpose of the Study:

  • To investigate the role of protein arginine methyltransferase 1 (PRMT1) in FOXO1 regulation.
  • To elucidate the mechanism by which PRMT1 affects FOXO1 stability and function.
  • To determine the impact of PRMT1-mediated FOXO1 modification on apoptosis.

Main Methods:

  • In vitro and in vivo methylation assays using PRMT1 and FOXO1.
  • Small interfering RNA (siRNA) to silence PRMT1 expression.
  • Analysis of FOXO1 localization, ubiquitination, and degradation.
  • Assessment of apoptosis under oxidative stress conditions.
  • Expression of wild-type and mutant PRMT1 and FOXO1.

Main Results:

  • PRMT1 methylates FOXO1 at Arg248 and Arg250, inhibiting Akt phosphorylation at Ser253.
  • PRMT1 silencing enhances FOXO1 nuclear exclusion, polyubiquitination, and proteasomal degradation.
  • PRMT1 knockdown reduces oxidative-stress-induced apoptosis.
  • Expression of inactive PRMT1 mutant increases apoptosis resistance, reversed by phosphorylation-deficient FOXO1.

Conclusions:

  • Arginine methylation by PRMT1 acts as an inhibitory modification against Akt-mediated FOXO1 phosphorylation.
  • PRMT1-mediated methylation stabilizes FOXO1, preventing its degradation and influencing apoptosis.
  • This study reveals a novel regulatory mechanism for FOXO transcription factors.

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