Metabolite Signaling Mediates Cellular Homeostasis and Proliferation
Nutrients and metabolites can both positively and negatively regulate cell signaling and anabolic metabolism. These signaling properties suggest that metabolites can influence both proliferation and cellular homeostasis. Here we describe a role for asparagine as an amino acid exchange factor: intracellular asparagine exchanges with extracellular amino acids. We show that intracellular asparagine levels regulate uptake of amino acids, especially serine, arginine, and histidine. Through its exchange factor role, asparagine promotes mTORC1 activity and downstream anabolic metabolism. In addition, we show that asparagine depletion may be sensed through intracellular lactate accumulation. Asparagine depletion impairs trafficking of lactate transporters MCT1 and MCT4 to decrease lactate export. We also provide evidence that lactate binds to and stabilizes ATF4, the transcription factor responsible for asparagine synthetase expression, suggesting that lactate, as a signal of asparagine depletion, is sensed by ATF4 to restore intracellular asparagine. In addition to stimulating ATF4 activity and ASNS expression, we find that lactate inhibits mTORC1 activity in an ATF4-dependent manner. Given the role of asparagine in amino acid uptake, our data suggest that lactate may be a novel signal to communicate amino acid deficiency to mTORC1. We propose that the cell coordinates anabolism with nutrient availability by linking ATF4 transcriptional activity to mTORC1 inhibition, such that lactate-induced mTORC1 inhibition upon asparagine depletion coincides with ATF4-mediated asparagine regeneration and is relieved upon asparagine restoration. Finally, we hypothesize that lactate signaling may explain why lactate export is a cancer hallmark: cancer cell lactate export both relieves cell-autonomous restrictions on mTORC1-mediated anabolism and enables exploitation of the tumor microenvironment through tumor-generated paracrine lactate signaling.