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The mammalian target of rapamycin (mTOR) is the central regulator of mammalian cell growth, and is essential for the formation of two structurally and functionally distinct complexes: mTORC1 and mTORC2. mTORC1 can sense multiple cues such as nutrients, energy status, growth factors and hormones to control cell growth and proliferation, angiogenesis, autophagy, and metabolism. As one of the key environmental stimuli, amino acids (AAs), especially leucine, glutamine and arginine, play a crucial role in mTORC1 activation, but where and how AAs are sensed and signal to mTORC1 are not fully understood. Classically, AAs activate mTORC1 by Rag GTPases which recruit mTORC1 to lysosomes, where AA signaling initiates. Plasma membrane transceptor L amino acid transporter 1 (LAT1)-4F2hc has dual transporter-receptor function that can sense extracellular AA availability upstream of mTORC1. The lysosomal AA sensors (PAT1 and SLC38A9) and cytoplasmic AA sensors (LRS, Sestrin2 and CASTOR1) also participate in regulating mTORC1 activation. Importantly, AAs can be sensed by plasma membrane receptors, like G protein-coupled receptor (GPCR) T1R1/T1R3, and regulate mTORC1 without being transported into the cells. Furthermore, AA-dependent mTORC1 activation also initiates within Golgi, which is regulated by Golgi-localized AA transporter PAT4. This review provides an overview of the research progress of the AA sensing mechanisms that regulate mTORC1 activity.

Since human Nucleoside Transporters (hNTs) were identified by their activity as transport systems, extensive work has been done to fully characterize them at the molecular and physiological level. Many efforts have been addressed to the identification of their selectivity for natural substrates and nucleoside analogs used to treat several diseases. hNTs belong to two different gene families, and , encoding human Concentrative Nucleoside Transporters (hCNTs) and human Equilibrative Nucleoside Transporters (hENTs), respectively. hCNTs and hENTs are integral membrane proteins, albeit structurally unrelated. Both families share common features as substrate selectivity and often tissue localization. This apparent biological redundancy may anticipate some different roles for hCNTs and hENTs in cell physiology. Thus, hENTs may have a major role in maintaining nucleoside homeostasis, whereas hCNTs could contribute to nucleoside sensing and signal transduction. In this sense, the ascription of hCNT1 to a transceptor reinforces this hypothesis. Moreover, some evidences could suggest a putative role of hCNT2 and hCNT3 as transceptors. The interacting proteins identified for hCNT2 suggest a link to energy metabolism. Moreover, the ability of hCNT2 and hCNT3 to transport adenosine links both proteins to purinergic signaling. On the other hand, the broad selectivity transporters hENTs have a crucial role in salvage pathways and purinergic signaling by means of nucleoside pools regulation. In particular, the two new hENT2 isoforms recently described together with hENT2 seem to be key elements controlling nucleoside and nucleotide pools for DNA synthesis. This review focuses on all these NTs functions beyond their mere translocation ability.

Transporters are at the centre of regulatory modules allowing optimal assimilation, distribution or efflux of substrate molecules. The IRT1 root metal transporter represents a textbook example in which detailed regulatory networks have been shown to integrate several endogenous and exogenous cues at various levels to regulate its expression and to fine tune iron uptake. Here, we summarise recent advances in the dissection of the transcriptional and posttranslational control of IRT1 by its various metals substrates and discuss the emerging role of IRT1 in the direct sensing of non-iron metals flowing through IRT1 to drive its degradation. We propose that transporters that also act as receptors are likely to be a common theme in the regulation of nutrient transport by sensing local nutrient concentrations.

Transporters of the SLC38 family are found in all cell types of the body. They mediate Na + -dependent net uptake and efflux of small neutral amino acids. As a result they are particularly expressed in cells that grow actively, or in cells that carry out significant amino acid metabolism, such as liver, kidney and brain. SLC38 transporters occur in membranes that face intercellular space or blood vessels, but do not occur in the apical membrane of absorptive epithelia. In the placenta, they play a significant role in the transfer of amino acids to the foetus. Members of the SLC38 family are highly regulated in response to amino acid depletion, hypertonicity and hormonal stimuli. SLC38 transporters play an important role in amino acid signalling and have been proposed to act as transceptors independent of their transport function. The structure of SLC38 transporters is characterised by the 5 + 5 inverted repeat fold, which is observed in a wide variety of transport proteins.

PQLC2, a lysosomal cationic amino acid transporter, also serves as a sensor that responds to scarcity of its substrates by recruiting a protein complex composed of C9orf72, SMCR8, and WDR41 to the surface of lysosomes. This protein complex controls multiple aspects of lysosome function. Although it is known that this response to changes in cationic amino acid availability depends on an interaction between PQLC2 and WDR41, the underlying mechanism for the regulated interaction is not known. In this study, we present evidence that the WDR41–PQLC2 interaction is mediated by a short peptide motif in a flexible loop that extends from the WDR41 β-propeller and inserts into a cavity presented by the inward-facing conformation of PQLC2. The data support a transceptor model wherein conformational changes in PQLC2 related to substrate transport regulate the availability of the WDR41-binding site on PQLC2 and mediate recruitment of the WDR41-SMCR8-C9orf72 complex to the surface of lysosomes.

Background: Tumor cells can reprogram their metabolism, constituting a hallmark of cancer that plays a crucial role in tumor progression. As tumor cells exhibit an increased demand for nutrients, e.g., amino acids, they rely on extracellular sources and show deregulation of transport proteins. Among these, SNAT1 (SLC38A1) is described as the loader for glutamine that is responsible for the main influx of this amino acid. The aim of this study was to assess the molecular function of SNAT1 in melanoma regarding its role in amino acid transport and regulation of cellular metabolism. Methods: siPool-mediated downregulation of SNAT1 expression in melanoma cell lines was used to investigate the molecular function of this protein. Glutamine transport was assessed by measuring the intracellular and extracellular concentrations of glutamine. Regulation of downstream effectors was evaluated with qRT-PCR and Western Blot. Metabolism was investigated by performing Seahorse flux analysis. Mitochondrial staining was examined via flow cytometry. Protein interaction was assessed with Co-IP, and in silico modeling of protein interaction was performed with AlphaFold3. Results: In this study, we uncovered the new finding that SNAT1 is not primarily implicated in glutamine influx into melanoma cells but in signaling in response to extracellular glutamine. We identified P62 and cMYC as downstream effectors of SNAT1. By activating the P62/cMYC-axis and target genes of cMYC, SNAT1 modulates the metabolism of melanoma cells depending on the glutamine level. SNAT1 and P62 are interaction partners. Conclusions: This finding newly suggests that SNAT1 may function as a sensor or receptor (“transceptor”) for glutamine rather than being a direct and primary glutamine transporter, and could open up new therapeutic options targeting melanoma cells.

The smut Ustilago maydis, a ubiquitous pest of corn, is highly adapted to its host to parasitize on its organic carbon sources. We have identified a hexose transporter, Hxt1, as important for fungal development during both the saprophytic and the pathogenic stage of the fungus. Hxt1 was characterized as a high-affinity transporter for glucose, fructose, and mannose; ∆hxt1 strains show significantly reduced growth on these substrates, setting Hxt1 as the main hexose transporter during saprophytic growth. After plant infection, ∆hxt1 strains show decreased symptom development. However, expression of a Hxt1 protein with a mutation leading to constitutively active signaling in the yeast glucose sensors Snf3p and Rgt2p results in completely apathogenic strains. Fungal development is stalled immediately after plant penetration, implying a dual function of Hxt1 as transporter and sensor. As glucose sensors are only known for yeasts, ‘transceptor’ as Hxt1 may constitute a general mechanism for sensing of glucose in fungi. In U. maydis, Hxt1 links a nutrient-dependent environmental signal to the developmental program during pathogenic development.

α-Ketoglutarate (AKG) is a crucial intermediate in the tricarboxylic acid (TCA) cycle and can be used for the production of ATP and amino acids in animal tissues. However, the effect of AKG on the expression patterns of genes involved in muscle protein metabolism is largely unknown, and the underlying mechanism remains to be elucidated. Therefore, we used young pigs to investigate the effects of a low crude protein (CP) diet and a low CP diet supplemented with AKG on protein accretion in their skeletal muscle. A total of 27 growing pigs with an initial body weight of 11.96 ± 0.18 kg were assigned randomly to one of the three diets: control (normal recommended 20% CP, NP), low CP (17% CP, LP), or low CP supplemented with 1% AKG (ALP). The pigs were fed their respective diets for 35 days. Free amino acid (AA) profile and hormone levels in the serum, and the expression of genes implicated in protein metabolism in skeletal muscle were examined. Results showed that compared with the control group or LP group, low-protein diets supplemented with AKG enhanced serum and intramuscular free AA concentrations, the mRNA abundances of AA transporters, and serum concentrations of insulin-like growth factor-1 (IGF-1), activated the mammalian target of rapamycin (mTOR) pathway, and decreased serum urea concentration and the mRNA levels for genes related to muscle protein degradation ( P  < 0.05). In conclusion, these results indicated that addition of AKG to a low-protein diet promotes amino acid synthesis in tissues and improves protein metabolism in skeletal muscle.

Nitrate functions as both a nutrient and a signaling molecule in plants, initiating genome-wide transcriptional reprogramming and systemic developmental adjustments. Traditionally, plasma membrane nitrate sensing and nuclear transcriptional responses have been considered independent processes linked through linear transduction pathways. However, recent findings reveal that the dual-affinity nitrate transceptor NRT1.1 (NPF6.3) and the transcription factor NLP7 form an integrated signaling nexus—the Nitrate transporter 1.1 (NRT1.1)-NIN-like protein 7 (NLP7) nexus. This review examines the coupling mechanisms, including Ca2+-dependent phosphorylation cascades, nucleocytoplasmic shuttling, and a recently discovered MAPK amplification branch. We further explore the nexus’s conserved and diversified functions across crop species, and propose a three-tier rational design framework for reprogramming nitrate responses to enhance nitrogen use efficiency. By bridging structural biology and synthetic biology, this integrative perspective transitions crop improvement from empirical selection to structure-guided design, offering a roadmap for predictive crop engineering.

The nutrient composition of the medium has dramatic effects on many cellular properties in the yeast . In addition to the well-known specific responses to starvation for an essential nutrient, like nitrogen or phosphate, the presence of fermentable sugar or a respirative carbon source leads to predominance of fermentation or respiration, respectively. Fermenting and respiring cells also show strong differences in other properties, like storage carbohydrate levels, general stress tolerance and cellular growth rate. However, the main glucose repression pathway, which controls the switch between respiration and fermentation, is not involved in control of these properties. They are controlled by the protein kinase A (PKA) pathway. Addition of glucose to respiring yeast cells triggers cAMP synthesis, activation of PKA and rapid modification of its targets, like storage carbohydrate levels, general stress tolerance and growth rate. However, starvation of fermenting cells in a glucose medium for any essential macro- or micro-nutrient counteracts this effect, leading to downregulation of PKA and its targets concomitant with growth arrest and entrance into G0. Re-addition of the lacking nutrient triggers rapid activation of the PKA pathway, without involvement of cAMP as second messenger. Investigation of the sensing mechanism has revealed that the specific high-affinity nutrient transporter(s) induced during starvation function as transporter-receptors or transceptors for rapid activation of PKA upon re-addition of the missing substrate. In this way, transceptors have been identified for amino acids, ammonium, phosphate, sulfate, iron, and zinc. We propose a hypothesis for regulation of PKA activity by nutrient transceptors to serve as a conceptual framework for future experimentation. Many properties of transceptors appear to be similar to those of classical receptors and nutrient transceptors may constitute intermediate forms in the development of receptors from nutrient transporters during evolution. The nutrient-sensing transceptor system in yeast for activation of the PKA pathway has served as a paradigm for similar studies on candidate nutrient transceptors in other eukaryotes and we succinctly discuss the many examples of transceptors that have already been documented in other yeast species, filamentous fungi, plants, and animals, including the examples in human cells.