mTORC1 as the main gateway to autophagy

Abstract

Cells and organisms must coordinate their metabolic activity with changes in their environment to ensure their growth only when conditions are favourable. In order to maintain cellular homoeostasis, a tight regulation between the synthesis and degradation of cellular components is essential. At the epicentre of the cellular nutrient sensing is the mechanistic target of rapamycin complex 1 (mTORC1) which connects environmental cues, including nutrient and growth factor availability as well as stress, to metabolic processes in order to preserve cellular homoeostasis. Under nutrient-rich conditions mTORC1 promotes cell growth by stimulating biosynthetic pathways, including synthesis of proteins, lipids and nucleotides, and by inhibiting cellular catabolism through repression of the autophagic pathway. Its close signalling interplay with the energy sensor AMP-activated protein kinase (AMPK) dictates whether the cell actively favours anabolic or catabolic processes. Underlining the role of mTORC1 in the coordination of cellular metabolism, its deregulation is linked to numerous human diseases ranging from metabolic disorders to many cancers. Although mTORC1 can be modulated by a number of different inputs, amino acids represent primordial cues that cannot be compensated for by any other stimuli. The understanding of how amino acids signal to mTORC1 has increased considerably in the last years; however this area of research remains a hot topic in biomedical sciences. The current ideas and models proposed to explain the interrelationship between amino acid sensing, mTORC1 signalling and autophagy is the subject of the present review.

Keywords: amino acids; autophagy; lysosome; mTOR.

Figure 1. mTORC1 signalling links cellular growth with autophagy

A range of physiological signals affects the activation status of mTORC1, including growth factor signalling, cellular energy levels via AMP-activated kinase (AMPK), oxygen levels and nutrients, particularly amino acids. The activation of mTORC1 regulates a number of cellular processes that affect the metabolic state of the cell. Through different mechanisms, mTORC1 signalling inhibits autophagy while promoting cell growth by stimulating biosynthetic pathways, including the synthesis of proteins, lipids and nucleotides.

Figure 2. Models of amino acid-dependent mTORC1 regulation

The presence of free amino acids is essential for the activation of mTORC1. Leucine, glutamine and arginine signal to mTORC1 by different mechanisms. These include cytoplasmic sensors, amino acid transporters and v-ATPase on the lysosomal membrane. The amino acid transporters sense specific amino acids in different subcellular compartments and act in cooperation with cytosolic amino acid sensors to control the activity of mTORC1. Other transporters act as conduits bringing amino acids inside the cell. All these mechanisms work to control the nucleotide-loading status of either Rag GTPases or Rheb, the most proximal regulators of mTORC1. mTORC1 hubs controlled by Arf1 and Rab1A/PAT4 appear to be Rag independent and are therefore not under the control of the cytosolic sensors. Arf1 is typically found on Golgi membranes but is reported to control a lysosomal sensing complex.

Figure 3. Amino acid-dependent regulation of autophagy by mTORC1

Schematic representation of the cellular signalling pathways governed by amino acids in the regulation of autophagy via mTORC1. Amino acid sufficiency activates the mTORC1 pathway which inhibits autophagy at multiple steps. Although the best-characterized mechanism via which mTORC1 inhibits autophagy involves the direct control of ULK1, mTORC1 also regulates Atg14-containing Vps34 complex and TFEB. In amino acid-rich conditions, mTORC1 binds to, phosphorylates and thereby inactivates the autophagy initiators ULK1 and Atg13, which are present in a complex with FIP200 and Atg101. Likewise, mTORC1 phosphorylates TFEB and TFE3 and this event facilitates the interaction between TFEB and TFE3 and the cytosolic chaperone 14-3-3 which retains them in the cytoplasm. In the absence of activating stimuli, autophagy is induced through the dissociation of mTORC1 from the ULK1 complex, thus relieving the inhibition of ULK1 which is then responsible of its own phosphorylation as well as phosphorylation of Atg13, FIP200 and Raptor. ULK1 is then able to activate this PI3K complex and promote autophagosome synthesis. In addition, mTORC1 inactivation leads to relocalization of TFEB and TFE3 to the nucleus where they cause the expression of multiple lysosomal and autophagy-related genes. This allows the cell to maintain a critical level of energy and metabolites for surviving the starvation condition.