The Circadian Protein Period2 Suppresses mTORC1 Activity via Recruiting Tsc1 to mTORC1 Complex

Area of Science:

• Molecular Biology
• Chronobiology
• Cellular Metabolism

Background:

• The circadian clock regulates daily rhythms in various physiological processes.
• Mammalian target of rapamycin complex 1 (mTORC1) signaling controls protein synthesis, cell growth, and autophagy.
• The molecular link between the circadian clock and mTORC1 oscillation is not well understood.

Purpose of the Study:

• To elucidate the mechanism by which the circadian clock protein Period2 (Per2) regulates mTORC1 signaling.
• To investigate the role of Per2 in controlling protein synthesis, cell proliferation, and autophagy.
• To identify the signaling pathway that induces Per2 expression in response to fasting in the liver.

Main Methods:

• Co-immunoprecipitation assays to assess protein interactions.
• Western blotting to measure protein levels and signaling pathway activation.
• Analysis of protein synthesis, cell proliferation, and autophagy markers in wild-type and Per2-deficient mice.
• In vivo studies involving fasting and glucagon administration.

Main Results:

• Period2 (Per2) acts as a scaffold protein, binding to tuberous sclerosis complex 1 (Tsc1), Raptor, and mTOR to inhibit mTORC1 activity.
• Per2 deficiency leads to increased protein synthesis and cell proliferation, alongside reduced autophagy.
• The glucagon-Creb/Crtc2 signaling pathway induces Per2 expression in the liver during fasting.
• Per2 mediates the fasting-induced suppression of mTORC1 in mouse liver.

Conclusions:

• Period2 is a novel regulator of mTORC1 signaling, linking the circadian clock to cellular metabolism.
• Per2 deficiency disrupts cellular homeostasis by enhancing protein synthesis and proliferation while impairing autophagy.
• The glucagon-Creb/Crtc2-Per2 axis represents a key mechanism for suppressing hepatic mTORC1 during fasting.