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FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor

Chia-Chen Chen1, Sang-Min Jeon, Prashanth T Bhaskar

  • 1Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.

Developmental Cell
|April 24, 2010
PubMed

Insights

Forkhead box O (FoxO) transcription factors regulate cellular energy by balancing Akt and mTORC1 activities. FoxO maintains high Akt and low mTORC1 activity during stress, preserving energy homeostasis.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Akt, FoxO transcription factors, and mTORC1 are key regulators of cellular metabolism and growth.
  • Understanding their interplay is crucial for comprehending cellular homeostasis.
  • Dysregulation of these pathways is implicated in various diseases, including cancer and metabolic disorders.

Purpose of the Study:

  • To elucidate the regulatory mechanisms governing the interactions between Akt, FoxO, and mTOR signaling pathways.
  • To investigate the role of FoxO in modulating the activities of mTORC1 and mTORC2.
  • To determine how FoxO influences cellular energy balance under stress conditions.

Main Methods:

  • Investigated gene expression changes induced by FoxO1, including Sestrin3 (Sesn3) and Rictor.
  • Assessed the impact of FoxO1 on mTORC1 and mTORC2 activity in both Tsc2-proficient and Tsc2-deficient cells.
  • Analyzed the effects of FoxO1-mediated signaling on Akt activation and cellular energy metabolism.

Main Results:

  • Activated FoxO1 inhibits mTORC1 through both TSC2-dependent and independent pathways, partly by inducing Sesn3 expression.
  • FoxO1 upregulates Rictor, enhancing mTORC2 activity and consequently activating Akt.
  • In Tsc2-deficient cells, FoxO1 promotes mTORC2 assembly and activity over mTORC1, leading to Akt activation and mTORC1 inhibition.

Conclusions:

  • FoxO transcription factors act as rheostats, maintaining a balance between Akt and mTOR complex activities.
  • Under physiological stress, FoxO promotes energy homeostasis by inhibiting the energy-consuming mTORC1 pathway while sustaining Akt activity.
  • These findings reveal a critical role for FoxO in coordinating cellular responses to stress and maintaining metabolic equilibrium.

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