Metabolite sensing and signaling in cell metabolism

Abstract

Metabolite sensing is one of the most fundamental biological processes. During evolution, multilayered mechanisms developed to sense fluctuations in a wide spectrum of metabolites, including nutrients, to coordinate cellular metabolism and biological networks. To date, AMPK and mTOR signaling are among the best-understood metabolite-sensing and signaling pathways. Here, we propose a sensor-transducer-effector model to describe known mechanisms of metabolite sensing and signaling. We define a metabolite sensor by its specificity, dynamicity, and functionality. We group the actions of metabolite sensing into three different modes: metabolite sensor-mediated signaling, metabolite-sensing module, and sensing by conjugating. With these modes of action, we provide a systematic view of how cells sense sugars, lipids, amino acids, and metabolic intermediates. In the future perspective, we suggest a systematic screen of metabolite-sensing macromolecules, high-throughput discovery of biomacromolecule-metabolite interactomes, and functional metabolomics to advance our knowledge of metabolite sensing and signaling. Most importantly, targeting metabolite sensing holds great promise in therapeutic intervention of metabolic diseases and in improving healthy aging.

Fig. 1

The model of metabolite sensing and signaling. a AMPK-mediated energy sensing and signaling. ACC, acetyl-CoA carboxylase; GLUT, glucose transporter. b mTOR-induced amino acid sensing and signaling. 4E-BP, eukaryotic translation initiation factor 4E-binding protein; S6K, ribosomal protein S6 kinase. c A working model composed of metabolite sensor (orange), signal transducer (blue), and effector (green). M indicates metabolite

Fig. 2

Metabolite sensor-mediated signaling. a Aldolase senses FBP and signals to AMPK. FBP, fructose 1,6-bisphosphate; V-ATPase, vacuolar-type H⁺-ATPase; Ragulator, protein complex that interacts with the Rag GTPases; LKB1, liver kinase B1. b Sestrin, CASTOR1, and SAMTOR mediate the sensing and signaling of leucine, arginine, and SAM, respectively. GATOR1/2, GATOR complex 1/2; Rag, Rag GTPases; SLC38A9, an amino acid transporter, also functions as a putative arginine sensor. c DBC1 signals NAD⁺ level to PARP1

Fig. 3

Metabolite-sensing module mediates metabolite signaling. a NDRG3 mediates lactate sensing. VHL, Von Hippel–Lindau tumor suppressor; c-Raf, RAF proto-oncogene serine/threonine-protein kinase; ERK, extracellular signal-regulated kinase. b LKB1-AMPK complex mediates Ru5P sensing. Ru5P, ribulose -5-phosphate. c SERCA and ER mediate PEP sensing and anti-tumor signaling in T cells. PEP, phosphoenolpyruvate; SERCA, sarco/endoplasmic reticulum Ca-ATPase; NFAT, Nuclear factor of activated T cells. The yellow dotted box indicates the metabolite-sensing module

Fig. 4

Metabolite sensing by conjugating. a Scheme of modification of proteins by metabolites. Prenyl-PP, prenyl diphosphate; Ac-CoA, acetyl-CoA; GlcNAc-UDP, uridine diphosphate N-acetylglucosamine. b Proteins are conjugated with sugar, lipid, amino acid and metabolic intermediates. The boxes indicate which metabolites are covalently linked to proteins