Nutrient sensors and their crosstalk

Abstract

The macronutrients glucose, lipids, and amino acids are the major components that maintain life. The ability of cells to sense and respond to fluctuations in these nutrients is a crucial feature for survival. Nutrient-sensing pathways are thus developed to govern cellular energy and metabolic homeostasis and regulate diverse biological processes. Accordingly, perturbations in these sensing pathways are associated with a wide variety of pathologies, especially metabolic diseases. Molecular sensors are the core within these sensing pathways and have a certain degree of specificity and affinity to sense the intracellular fluctuation of each nutrient either by directly binding to that nutrient or indirectly binding to its surrogate molecules. Once the changes in nutrient levels are detected, sensors trigger signaling cascades to fine-tune cellular processes for energy and metabolic homeostasis, for example, by controlling uptake, de novo synthesis or catabolism of that nutrient. In this review, we summarize the major discoveries on nutrient-sensing pathways and explain how those sensors associated with each pathway respond to intracellular nutrient availability and how these mechanisms control metabolic processes. Later, we further discuss the crosstalk between these sensing pathways for each nutrient, which are intertwined to regulate overall intracellular nutrient/metabolic homeostasis.

Fig. 1. Glucose sensors.

Glucose can be sensed by GCK, GLUT2, and aldolase. When glucose is supplemented at a high level, it is phosphorylated by GCK, a hexokinase protein, to produce ATP. Under glucose deprivation, GCK interacts with BAD in the mitochondria. GCK phosphorylates BAD to promote the reduction of apoptosis. GLUT2 takes up glucose only when the glucose level is high. As glucose is imported by GLUT2, GLUT2 will increase the intracellular calcium level to secrete insulin. Under low-glucose conditions, free aldolase proteins localize in the lysosomal membrane, inhibiting TRPV channels and forming a V-ATPase-Ragulator complex stabilized by LKB1-Axin. This complex initiates the activation of AMPK for downstream signaling pathways. Under high-glucose conditions, FBP levels are increased. FBP binds to aldolase, which inhibits its localization and complex formation in the lysosome.

Fig. 2. mTORC1-related amino acid sensors.

Leucine is sensed by LARS1 and sestrin2. Leucine-bound LARS1 activates mTORC1 through the RagGTP pathway, and leucine-bound sestrin2 inhibits GATOR2, which stimulates the mTORC1 complex. The methionine derivative metabolite S-adenosylmethionine is sensed by SMATOR. SAMTOR binds SAM at the GATOR-KICSTOR binding domain. This will allow GATOR1 to be inactivated and inhibit its GAP activity to stimulate mTORC1 function. Arginine-bound TM4SF5 induces SLC38A9 to pump arginine out of the lysosomal membrane. Increased arginine concentration allows the binding of arginine to CASTOR1, which induces the dissociation of GATOR2 from CASTOR1, increasing the activity of mTORC1. Threonine also becomes charged to TARS2. This protein interacts with RagC and activates GEF function to produce RagA-GTP, which activates the mTORC1 complex. Although the sensor has not yet been discovered, glutamine-derived alpha-ketoglutarate seems to induce mTORC1 activation by Arf1.

Fig. 3. Leucine-sensing mechanism.

Increased leucine concentration is sensed by different proteins to activate the mTOR pathway. When the leucine concentration is sufficiently high, LARS1 has leucine bound in the amino acid-binding site. This induces the activation of the leucine-dependent GTPase-activating protein function of LARS1. This hydrolysis of RagD-GTP results in RagD-GDP/RagB-GTP, which activates mTORC1. Leucine-bound LARS1 also interacts with Vps34. This activates the production of PI-3-P, which binds with PLD1 in the lysosome. PI-3-P-bound PLD1 activates mTORC1 through interaction with the Rheb protein. Sestrin2 also functions as a leucine sensor. Leucine-bound sestrin2 dissociates from GATOR2. Activated GATOR2 binds with GATOR1 to inhibit its function. The Rag GTPase negative regulator GATOR1 will end and activate RagA-GTP/RagC-GDP to increase the activity of mTORC1.

Fig. 4. Lipid sensors.

A Under cholesterol deprivation, cholesterol-unbound SCAP dissociates from INSIG (not shown), which favors SCAP-SREBP complex translocation from the ER to the Golgi. Subsequently, the cytoplasmic domain of SREBP is released by proteolytic cleavage, leading to the induction of key enzymes in cholesterol biosynthesis in the nucleus. B HMGCR is embedded in the ER and is responsible for the rate-limiting step in the de novo synthesis of cholesterol, which is especially important when low intracellular cholesterol levels are present. When intermediate sterol species, such as lanosterol, accumulate during the biosynthesis of cholesterol, HMGCR interacts with INSIG and the ubiquitination complex comprising VCP, gp78 and Ubc7. This interaction leads to the ubiquitination and subsequent degradation of HMGCR to immediately halt cholesterol synthesis. C Long-chain fatty acids are imported by membrane transporters, such as CD36. Fatty acids in the cytosol enter mitochondria by CPT1 on the outer membrane of mitochondria. CPT1 converts long chain acyl-CoA into acyl-carnitines, and this process is critical for FAO. Excess fatty acids synthesized by the cell are sensed by CPT1 via malonyl-CoA, the intermediate precursor of fatty acid synthesis, as the signal. Fluctuations in intracellular FAs can also be sensed by PPARs in the nucleus. Diverse species of FAs are capable of binding to the ligand binding domain in PPARs. Once activated, PPARs interact with various coactivators and induce the transcription of key regulatory genes in FAO and lipogenesis.

Fig. 5. Crosstalk of nutrient sensors.

A LARS1 and aldolase crosstalk with each other to control leucine and glucose availability, respectively. Under a limited-glucose environment, free aldolase allows the activation of AMPK, and OGT1 O-GlcNAcylates LARS1. AMPK phosphorylates ULK1. Activated ULK1 phosphorylates O-GlcNAc-LARS1. This inhibits the binding of leucine to LARS1 and modifies the fate of leucine to ATP synthesis instead of the activation of mTORC1 for protein synthesis. B Fatty acids and glucose are sensed by CPT1 and AMPK, respectively, for their crosstalk. Under nutrient supplementation, aldolase AMPK becomes inhibited, and as fatty acids are sufficiently supplemented, ACC activation is initiated by the allosteric activator citrate. ACC activation suppresses CPT1 function, which allows the production of malonyl-CoA to accumulate excess energy.