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Gollwitzer et al. and Figlia et al. establish that the different Rag GTPase genes and isoforms differentially regulate mTORC1 activity and distinctly modulate the responsiveness of mammalian cells to amino acid availability.

Fernandes, Angelidaki et al. provide evidence supporting the spatial separation of mTORC1 activation and signalling. Differentially localized mTORC1 complexes phosphorylate distinct substrates in response to different amino acid supplies.

Cryogenic-electron microscopy is used to determine the structure of TFEB as presented to mTORC1 for phosphorylation and an explanation is found for the strong dependence of TFEB phosphorylation on FLCN and the RagC GDP state.

Phagocytosed bacteria can serve as an alternative nutrient source for macrophages, influencing their metabolic and immune responses through the recycling of microbial components, with the process regulated by nutrient-sensing mechanisms and bacterial viability.

Porphyromonas gingivalis, an oral anaerobe involved in the pathogenesis of periodontitis, relies on extracellular proteases to degrade proteins into peptides for growth, but how these peptides enter the cell is unknown. Here, the authors identify RagAB as the outer-membrane importer for these peptides and solve its structure, elucidating that it works via a ‘pedal bin’ mechanism of nutrient uptake.

Cryo-EM structures of Rag GTPases in complex with Ragulator and the cytoplasmic tail of the lysosomal solute carrier SLC38A9 show how SLC38A9 promotes Rag dimer activation, essential for mTORC1 recruitment to the lysosomal membrane.

Cryo-electron microscopy was used to study human mechanistic target of rapamycin complex 1 (mTORC1) activation on lysosomal membranes, showing progressive recruitment by RAG–Ragulator, RHEB and RAPTOR, culminating in mTOR–membrane engagement and full enzyme activation.

Dysregulation of an mTORC1 substrate-specific mechanism leads to constitutive activation of TFEB, and promotes kidney cystogenesis and tumorigenesis in a mouse model of Birt–Hogg–Dubé syndrome.

The taurine–taurine transporter axis is a critical dependency of aggressive myeloid leukaemias.

RagGTPases (Rags) play an essential role in the regulation of cell metabolism by controlling the activities of both mechanistic target of rapamycin complex 1 (mTORC1) and Transcription factor EB (TFEB). Here the authors review several diseases, termed ragopathies, that are associated with Rag dysfunction.

Ong et al. report how YAP/TAZ and mTORC1 signalling intersect in endothelial cells to regulate nutrient acquisition and vascular growth.

Amino acids are one of the key environmental stimuli signalling to mTOR. Although exactly how they are sensed and how they activate mTOR has remained elusive, a model has emerged that implicates signalling by RAG GTPases, Ragulator and v-ATPase at the lysosome and leucyl t-RNA synthetase in the cytoplasm.

Nicastro, Brohée et al. find that the fatty acid synthesis intermediate malonyl-CoA inhibits mTORC1, showing mTORC1 senses the capacity of a cell to synthesise fatty acids and linking fatty acid generation with the overall biosynthetic output through mTORC1.

Mutations in the RRAGD gene are causative of an autosomal dominant disorder characterized by kidney tubulopathy and cardiomyopathy. Here, the authors identify a new RRAGD P88L mutation, demonstrating that all the identified RRAGD mutations inhibit the nuclear translocation of MiT/TFE transcription factors, resulting in defective responses to lysosomal or mitochondrial damage.

The mTORC1 protein kinase complex integrates nutrient and growth stimuli to modulate signalling pathways that regulate cellular metabolism and physiology, but the molecular nature of the amino acid sensing mechanism at the lysosome is unknown; here, an orphan member of the human solute carrier group of proteins, SLC38A9, is shown to be an integral component of the lysosomal machinery that can directly sense amino acids and activate mTORC1.

Budding yeast use multilayered regulation by Ait1, Gcn2, and the SEAC/GATOR complex to control TORC1 activity. This circuit design ensures that cells can adapt to low-quality nitrogen sources or shut down growth during starvation.

Determination of the high-resolution structure of yeast TORC1 allows characterization of the precise interfaces of interaction between inactive TORC1 and TORC1′ polymers and identification of the mode of binding of active EGOC on TORC1.

Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and tumors in multiple organs. Here, the authors show that TFEB is the primary driver of renal disease and mTORC1 hyperactivation in TSC.

In a mouse model of breast cancer, a low-protein diet induces engulfment activities and mTORC1 signalling in tumour-associated macrophages to suppress engulfment-dependent mTORC1 signalling in MYC-overexpressing cancer cells through cell competition, serving as an innate immune defence mechanism to slow tumour growth.

In the nematode C. elegans, cohesin creates specifically at active enhancers chromatin 3D structures named fountains. Cohesin artificial cleavage disrupts fountains and changes neuronal gene expression, function and animal behavior.

Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.

Amino acids stimulate cell growth and depletion in a cell activates autophagy, yet how this is regulated is unclear. Here, the authors show that MAP4K3 (also known as germinal-center kinase-like kinase) acts as an amino acid-dependent regulator of autophagy, via phosphorylation of the transcription factor EB.

A covalent ligand that targets C277 of ATP6V1A was identified resulting in enhanced v-ATPase activity, inhibition of mTORC1 signaling, increased lysosomal acidification, activation of autophagy and clearance of toxic protein aggregates.

Lysosomes orchestrate key cellular functions such as nutrient sensing, degradation of macromolecules and stress adaptation. This Review discusses the integration of signalling pathways at the lysosome and highlights the interaction of lysosomes with other organelles and mechanisms that ensure lysosome homeostasis.

Nakamura et al. find that the master transcriptional regulator of lysosomal biogenesis and autophagy TFEB is activated following LC3 lipidation during lysosomal damage and show the importance of this mechanism during kidney injury.

ALMA has captured exquisitely detailed images of bowshock shells in the outflow of an outbursting protostar. These provide important insights into the variable nature of the ejections from protostars, which play a key role in star and planet formation.

Cai et al. show that, in lysosomes under hydrostatic pressure in macrophages, lysosomal mechanosensitive channels cause a cation leak. This leads to the inhibition of mTORC1, activation of TFEB/TFE3 and release of monocyte chemoattractant proteins.

Leucyl-tRNA synthetase (LRS) is a leucine sensor of the mTORC1 pathway. Here, the authors identify inhibitors of the GTPase activating function of LRS, not affecting its catalytic activity, and demonstrate that the leucine sensor function of LRS can be a new target for mTORC1 inhibition.

In this study, Vergani-Junior et al. show that increased expression of the argonaute ALG-1 in long-lived worms improves oxidative stress resistance through the modulation of microRNAs that downregulate the protein disulfide isomerase pathway.

Axonal spheroids disrupt neural circuits in Alzheimer’s disease. In this study, using subcellular proximity labeling proteomics in human brain and iPSC modeling, the authors link spheroid formation to dysregulated mTOR, cytoskeletal and lipid transport signaling.

The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1. Here, authors demonstrate that TFEB is paradoxically hypophosphorylated and activated in cells with TSC2 loss due to impaired lysosomal recruitment of the FLCN:FNIP2 complex in renal cells.

Our understanding of the downstream effectors and upstream regulators of target of rapamycin (TOR) signalling continues to grow. In particular, recent global 'omics' studies have revealed physiological roles of mammalian TOR (mTOR) in protein, nucleotide and lipid synthesis, and other studies showed that Hippo, WNT and Notch signalling are novel regulators of mTOR.

The cryo-electron microscopy structure of C9orf72–SMCR8–WDR41 suggests that this complex is a GTPase-activating protein for ARF-family small GTPases, which sheds light on the role of C9orf72 mutations in neuronal dysfunction.

The 3D structure of the human nutrient-sensing complex GATOR2 is resolved using cryo-electron microscopy.

The mammalian target of rapamycin (mTOR) controls cell growth and size. Amino acids are known to activate TOR, and Rag (Ras-related GTP-binding protein) GTPases have now been found to act as their effectors.

Eight genome-wide CRISPR screens identify genes required for substrate-specific phagocytosis. The study highlights roles for NHLRC2 in filopodia formation, very-long-chain fatty acids in substrate-specific phagocytosis and TM2D3 in uptake of amyloid-β aggregates.

This Brain Somatic Mosaicism Network analysis of 283 cases of malformations of cortical development identifies 69 candidate and known genes in 76 patients. Single-nucleus RNA sequencing and mouse modeling implicate radial glia and daughter excitatory neurons.

Ndeh et al. show that a genetic locus in the human gut bacterium, Bacteroides thetaiotaomicron, encodes a combination of glycosidases, a glycoprotease and a kinase enabling it to process and metabolise O-glycoproteins and the core mucin O-glycan sugar N-acetylgalactosamine.

The phase 3 STEER trial showed that a single intrathecal dose of onasemnogene abeparvovec significantly improved motor function in children and adolescents with spinal muscular atrophy versus sham, with a similar and acceptable safety profile.

Hodor, an intestinal zinc-gated chloride channel, controls systemic growth in Drosophila by promoting food intake and by modulating Tor signalling and lysosomal homeostasis within enterocytes.

The interaction between TASL and SLC15A4 links endolysosomal Toll-like receptors to the transcription factor IRF5, providing a mechanistic explanation for the involvement of the complex in systemic lupus erythematosus.

The cytosolic ubiquitin ligase Nedd4-1 is known to promote autophagy. Here, the authors characterize a primate-specific splice isoform, Nedd4-1(NE), that is localized to late endosomes in the presence of amino acids, where it inhibits autophagy.