mTOR regulation of autophagy

Abstract

Nutrient starvation induces autophagy in eukaryotic cells through inhibition of TOR (target of rapamycin), an evolutionarily-conserved protein kinase. TOR, as a central regulator of cell growth, plays a key role at the interface of the pathways that coordinately regulate the balance between cell growth and autophagy in response to nutritional status, growth factor and stress signals. Although TOR has been known as a key regulator of autophagy for more than a decade, the underlying regulatory mechanisms have not been clearly understood. This review discusses the recent advances in understanding of the mechanism by which TOR regulates autophagy with focus on mammalian TOR (mTOR) and its regulation of the autophagy machinery.

Figure 1

Regulation of the mTOR pathway by nutrients (amino acids, glucose), stress and insulin/IGF-1. (a) Two mTOR complexes, mTORC1 and mTORC2, and their components. mTORC1 is the protein complex responsible for autophagy induction in response to nutrient starvation, stress and reduced growth factor signaling. mTORC2 regulates autophagy via Akt-FoxO3 in skeletal muscle cells in response to a fasting condition [19,20]. (b) The signaling pathways upstream of mTORC1 that regulate cell growth and autophagy in response to nutrient levels, growth factors, and stress.

Figure 2

Comparison of the Atg1/ULK machinery between yeast and higher eukaryotes. (a) Current model for the mechanism by which TOR regulates the Atg1 complex in S. cerevisiae. TOR phosphorylates Atg13 at multiple residues resulting in disruption of the complex and inhibition of autophagy. (b) Comparison of the domain structures of S. cerevisiae Atg1, C. elegans UNC51, D. melanogaster Atg1, and Homo sapiens ULK1, ULK2, ULK3 and ULK4. (c) Phosphorylational regulation of ULK1/2 complexes by mTORC1 in response to nutrient levels. mTORC1 phosphorylates ULK1/2 and Atg13 and inhibits the kinase activity of ULK1/2 under high nutrient conditions. Under starvation, mTORC1 phosphorylation of ULK complex is suppressed releasing ULK from mTORC1 inhibition, which subsequently induces ULK to phosphorylate Atg13, FIP200 and itself.

Figure 3

(a) Two-state hypothesis for ULK1 conformation and activity. ULK1 interacts with Atg13, FIP200 and Atg101 through its C-terminal region [66,69,72,73,75]. Under high nutrient conditions, mTORC1 interacts with the ULK1 complex and phosphorylates ULK1 and Atg13 [66,71,72]. The phosphorylation may induce ULK1 to take an “open” conformation, an inactive form [69]. Under stress or starvation, mTORC1 is dissociated from the ULK1 complex. When mTORC1 could no longer phosphorylate ULK1 and Atg13 under the condition, ULK1 may take a “closed” conformation, an active form. In the closed-conformation state, the kinase domain of ULK1 may phosphorylate Atg13 and FIP200 and trigger the downstream events for autophagosome formation.