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

Although emerging evidence indicates an important role of the circadian clock in modulating the diurnal oscillation of mammalian target of rapamycin complex 1 (mTORC1) signaling, the underlying molecular mechanism remains elusive. Here we show that Period2 (Per2), a core clock protein, functions as a scaffold protein to tether tuberous sclerosis complex 1 (Tsc1), Raptor, and mTOR together to specifically suppress the activity of mTORC1 complex. Due to the loss of its inhibition of mTORC1, Per2 deficiency significantly enhances protein synthesis and cell proliferation but reduces autophagy. Furthermore, we find that the glucagon-Creb/Crtc2 signaling cascade induces Per2 expression, which mediates the suppression of mTORC1 in mouse liver during fasting. Our study not only uncovers a novel role of Per2 in regulating the mTORC1 pathway, but also sheds new light on the mechanism of fasting inhibition on mTORC1 in the liver.