The Dawn of the Age of Amino Acid Sensors for the mTORC1 Pathway

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that responds to a diverse set of environmental inputs, including amino acids. Over the past 10 years, a number of proteins have been identified that help transmit amino acid availability to mTORC1. However, amino acid sensors for this pathway have only recently been discovered. Here, we review these recent advances and highlight the variety of unexplored questions that emerge from the identification of these sensors.

Keywords: CASTOR; SLC38A9; Sestrin2; Sestrins; amino acid sensing; amino acid sensors; growth control; mTOR; mTORC1; nutrient sensing.

Figure 1

The amino acid sensing pathway upstream of mTORC1 Schematic detailing the key molecular players in the nutrient sensing branch upstream of mTORC1.

Figure 2

Bimodal regulation of Sestrin2 A) Sestrin2 is a leucine sensor and inhibitor of mTORC1 signaling in response to stresses. Sestrin2, leucine, and GATOR2 exist in a equilibrium in the cell that dictates mTORC1 activity in response to both leucine levels and other stresses. Increasing leucine levels pushes the Sestrin2-leucine equilibrium forward such that more GATOR2 is free, leading to increased mTORC1 signaling. Increasing levels of Sestrin2, downstream of ATF4 in response to cellular stresses, pushes the Sestrin2-GATOR2 equilibrium forward, inhibiting mTORC1 signaling. B) Schematic depicting mTORC1 activity in response to increasing Sestrin2 levels, at constant levels of GATOR2 and leucine. C) Diagram showing how modulating leucine levels will impact mTORC1 activity at varying cellular levels of Sestrin2.

Figure 3

Conservation of members of the nutrient sensing pathway across evolution Diagram depicting conservation of mTORC1 pathway members across evolution. Dark blue bars indicate that the protein is well conserved across the specified group or species, light blue bars indicate that the protein is conserved in many but not all organisms within the group, asterisks indicate conservation in only a few organisms within the group, and no bars indicate the protein is not conserved in the indicated group or organism.

Figure 4

mTORC1 signaling pathway conservation across evolution Cladogram showing conservation of members of the mTORC1 signaling in various organisms across evolution. Data are a subset of the organisms shown in Figure S1. Legend on the right side indicates colored bars for each gene. Locations of the three kingdoms (plants, fungi, and animals) are listed.