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Glycogen synthase kinase 3 drives thymocyte egress by suppressing β-catenin activation of Akt

Chenfeng Liu1, Lei Ma1, Yuxuan Wang1

  • 1State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.

Science Advances
|October 8, 2021
PubMed

Insights

Glycogen synthase kinase 3 (GSK3) is crucial for thymocyte egress. Inhibiting GSK3 impairs T cell exit from the thymus by affecting β-catenin signaling and downstream pathways.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Thymocyte emigration is essential for adaptive immunity.
  • Molecular mechanisms regulating thymocyte egress are not fully elucidated.

Purpose of the Study:

  • To investigate the role of glycogen synthase kinase 3 (GSK3) in thymocyte emigration.
  • To identify molecular pathways involved in GSK3-mediated thymocyte egress.

Main Methods:

  • T cell-specific ablation of GSK3 in mice.
  • Analysis of β-catenin localization and activity.
  • Assessment of Akt, Foxo1, Klf2, and S1P1 expression.
  • Genetic and viral rescue experiments.

Main Results:

  • GSK3 deficiency severely impaired thymocyte egress.
  • GSK3 ablation caused cytoplasmic accumulation and nuclear exclusion of β-catenin.
  • Cytoplasmic β-catenin activated Akt, leading to Foxo1 degradation and reduced Klf2/S1P1 expression.
  • Genetic interventions targeting β-catenin, Akt, or Foxo1 restored thymocyte emigration.

Conclusions:

  • GSK3 plays a critical role in regulating thymocyte emigration.
  • A novel cytoplasmic function of β-catenin, independent of transcriptional activity, is identified in thymocyte egress.
  • GSK3 controls thymocyte exit through a pathway involving β-catenin, Akt, and Foxo1.

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