Conceptualizing Eukaryotic Metabolic Sensing and Signaling

Abstract

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.