Conceptualizing Eukaryotic Metabolic Sensing and Signaling

For almost all cells, nutrient availability, from glucose to amino acids, dictates their growth or developmental programs. This nutrient availability is closely coupled to the overall intracellular metabolic state of the cell. Therefore, cells have evolved diverse, robust and versatile modules to sense intracellular metabolic states, activate signaling outputs and regulate outcomes to these states. Yet, signaling and metabolism have been viewed as important but separate. This short review attempts to position aspects of intracellular signaling from a metabolic perspective, highlighting how conserved, core principles of metabolic sensing and signaling can emerge from an understanding of metabolic regulation. I briefly explain the nature of metabolic sensors, using the example of the AMP activated protein kinase (AMPK) as an energy sensing hub. Subsequently, I explore how specific central metabolites, particularly acetyl-CoA, but also S-adenosyl methionine and SAICAR, can act as signaling molecules. I extensively illustrate the nature of a metabolic signaling hub using the specific example of the Target of Rapamycin Complex 1 (TORC1), and amino acid sensing. A highlight is the emergence of the lysosome/vacuole as a metabolic and signaling hub. Finally, the need to expand our understanding of the intracellular dynamics (in concentration and localization) of several metabolites, and their signaling hubs is emphasized.