Amino Acid Signaling for TOR in Eukaryotes: Sensors, Transducers, and a Sustainable Agricultural fuTORe

Abstract

Eukaryotic cells monitor and regulate metabolism through the atypical protein kinase target of rapamycin (TOR) regulatory hub. TOR is activated by amino acids in animals and fungi through molecular signaling pathways that have been extensively defined in the past ten years. Very recently, several studies revealed that TOR is also acutely responsive to amino acid metabolism in plants, but the mechanisms of amino acid sensing are not yet established. In this review, we summarize these discoveries, emphasizing the diversity of amino acid sensors in human cells and highlighting pathways that are indirectly sensitive to amino acids, i.e., how TOR monitors changes in amino acid availability without a bona fide amino acid sensor. We then discuss the relevance of these model discoveries to plant biology. As plants can synthesize all proteinogenic amino acids from inorganic precursors, we focus on the possibility that TOR senses both organic metabolites and inorganic nutrients. We conclude that an evolutionary perspective on nutrient sensing by TOR benefits both agricultural and biomedical science, contributing to ongoing efforts to generate crops for a sustainable agricultural future.

Keywords: Arabidopsis thaliana; Castor1; GATOR; GCN2; Ragulator; Sestrin2; amino acid signaling; mTOR; metabolism; target of rapamycin.

Figure 1

Sensors and transducers in metabolic signaling. (A) Metabolic signaling is triggered by a metabolite sensor protein that directly binds to a metabolite. The sensor then engages transducers in a signaling pathway that eventually activate responses through an effector protein. (B) In mammalian models, amino acids are sensed directly by diverse sensor proteins that activate the mechanistic target of rapamycin (mTOR), a central regulatory hub that transduces diverse upstream signals to coordinate metabolism. mTOR then phosphorylates additional transducers and effectors, such as LARP1 and S6K, to promote protein synthesis and repress autophagy.

Figure 2

Amino acid signaling in eukaryotes. In mammals, amino acids (red) are monitored by multiple sensors (orange) that engage transducers (blue) at multiple steps in the GATOR2–GATOR1–Ragulator–Rag GTPase signaling cascade to coordinate TOR (teal) activity at the surface of the lysosome. Very few of these signaling components are conserved in plants (gray indicates not conserved in plants). Sar1b and LARS, which have essential roles in membrane trafficking and tRNA synthesis, respectively, were exapted as amino acid sensors in the animal lineage and may not act as amino acid sensors in plants.

Figure 3

TOR monitors nitrogenous nutrient availability in plants. Plants can synthesize all 20 proteinogenic amino acids from inorganic precursors (nitrate or ammonium, carbon dioxide, and sulfate). N. benthamiana were grown on calcined clay and supplied with standard nutrients except for nitrogen, which was supplied as potassium nitrate at the indicated concentrations. Nitrate strongly stimulated plant growth and activated TOR, as measured by Western blots using phosphospecific antibodies against the canonical TOR substrate, S6K-pT449 (methods as in [13]).

Figure 4

TOR responds to nitrogen and amino acid metabolism in plants to coordinate growth and development [30], protein synthesis [6], and cytoskeletal function [27,28].