bims-raghud 2025-07-27 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2025–07–27
eight papers selected by
Irene Sambri, TIGEM

FNIP1 Deficiency: Pathophysiology and Clinical Manifestations of a Rare Syndromic Primary Immunodeficiency.
Targeting the Endocannabinoid System to Suppress mTORC1 Hyperactivation in TSC-associated Kidney Disease.
Sirtuins in mitophagy: key gatekeepers of mitochondrial quality.
mTORC1 senses glutamine and other amino acids through GCN2.
Human fetal kidney organoids model early human nephrogenesis and Notch-driven cell fate.
TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency.
Structural insights into cholesterol sensing by the LYCHOS-mTORC1 pathway.
The transcriptomic signature of DEPDC5 KO induced mTOR hyperactivation in human neurons and its response to rapamycin treatment.

Curr Issues Mol Biol. 2025 Apr 18. pii: 290. [Epub ahead of print]47(4):

FNIP1 Deficiency: Pathophysiology and Clinical Manifestations of a Rare Syndromic Primary Immunodeficiency.

Samuele Roncareggi, Brian M Iritani, Francesco Saettini.

  Folliculin-interacting protein 1 (FNIP1) is a key regulator of cellular metabolism and immune homeostasis, integrating nutrient signaling with proteostasis. FNIP1 forms a complex with folliculin (FLCN) to regulate the mechanistic target of rapamycin complex 1 (mTORC1), functioning as a GTPase-activating protein (GAP) for RagC/D. Additionally, FNIP1 interacts with heat shock protein 90 (HSP90) and undergoes phosphorylation, glycosylation, and ubiquitination, which dynamically regulate its stability and function. Evidence from murine models suggests that FNIP1 loss disrupts immune cell development and mitochondrial homeostasis. However, FNIP1 deficiency in humans remains incompletely characterized, and its full phenotypic spectrum is likely underestimated. Notably, FNIP1-deficient patients exhibit immunological and hematological abnormalities, immune dysregulation, and metabolic perturbations, emphasizing its role in cellular adaptation to stress. Understanding the mechanistic basis of FNIP1 dysfunction in human tissues will be critical for delineating its contributions to immune and metabolic disorders and identifying targeted interventions.

Keywords:  FNIP1 deficiency; agammaglobulinemia; hypertrophic cardiomyopathy; inborn error of immunity; neutropenia; primary immunodeficiency

DOI:  https://doi.org/10.3390/cimb47040290
Am J Physiol Renal Physiol. 2025 Jul 24.

Targeting the Endocannabinoid System to Suppress mTORC1 Hyperactivation in TSC-associated Kidney Disease.

Eden Abergel, Hadass Pri-Chen, Shulamit Wallach-Dayan, Liad Hinden, Joseph Tam, Oded Volovelsky, Morris Nechama.

  Tuberous Sclerosis Complex (TSC) promotes renal cyst formation and chronic kidney disease through mTORC1 dysregulation, yet effective treatments remain limited. Using mouse models with Tsc1 deletion in nephron progenitor cells and CRISPR-edited human kidney cells, we assessed the role of the endocannabinoid system in TSC-associated kidney disease. Tsc1 deletion led to significant alterations in endocannabinoid levels and the expression of metabolizing enzyme. These molecular changes were accompanied by receptor dysregulation, characterized by CB1R upregulation and CB2R downregulation in cyst-lining epithelial cells. A similar receptor imbalance was observed in TSC1-deficient human kidney cells, suggesting a conserved pathogenic mechanism. Treatment with the peripheral CB1R antagonist JD5037 significantly reduced mTORC1 activity and c-Myc expression in cultured cells and ex vivo kidney organ cultures. These findings identified CB1R as a potential therapeutic target, linking endocannabinoid dysregulation to TSC kidney pathology.

Keywords:  Cystic Kidney; Endocannabinoids; Tuberos Sclerosis; mTORC1

DOI:  https://doi.org/10.1152/ajprenal.00097.2025
Mol Cell Biochem. 2025 Jul 24.

Sirtuins in mitophagy: key gatekeepers of mitochondrial quality.

Francisco Alejandro Lagunas-Rangel.

  Mitochondria are highly dynamic organelles essential for cellular energy production. However, they are also a primary source of reactive oxygen species, making them particularly vulnerable to oxidative damage. To preserve mitochondrial integrity, cells employ quality control mechanisms such as mitophagy, a selective form of autophagy that targets damaged or dysfunctional mitochondria for degradation. Among the key regulators of mitophagy are the sirtuins, a family of NAD+-dependent deacetylases. SIRT1, SIRT3, and SIRT6 generally promote mitophagy, whereas SIRT2, SIRT4, SIRT5, and SIRT7 often act as negative regulators. Sirtuin-mediated regulation of mitophagy is critical for maintaining cellular homeostasis and is implicated in a variety of physiological and pathological conditions. The aim of this review is to provide an overview focused on describing how sirtuins influence the mitophagy process. It highlights the different molecular mechanisms by which individual members of the sirtuin family modulate mitophagy, either by promoting or suppressing it, depending on the context. In addition, the review explores the relevance of sirtuin-regulated mitophagy in health and disease, emphasizing some conditions under which altered sirtuin activity could be harnessed for therapeutic benefit.

Keywords:  FOXO transcription factors; Mitochondria; PINK1-PARKIN pathway; Receptor-mediated mitophagy; Ubiquitin-mediated mitophagy

DOI:  https://doi.org/10.1007/s11010-025-05358-0
EMBO J. 2025 Jul 21.

mTORC1 senses glutamine and other amino acids through GCN2.

Gianluca Figlia, Sandra Müller, Fabiola Garcia-Cortizo, Marilena Neff, Glynis Klinke, Gernot Poschet, Aurelio A Teleman.

  mTORC1 promotes cell growth when nutrients such as amino acids are available. While dedicated sensors relaying availability of leucine, arginine and methionine to mTORC1 have been identified, it is still unclear how mTORC1 senses glutamine, one of its most potent inducers. Here, we find that glutamine is entirely sensed through the protein kinase GCN2, whose initial activation is not triggered by depletion of glutamine itself, but by the concomitant depletion of asparagine. In turn, GCN2 leads to a succession of events that additively inhibit mTORC1: within 1 h, GCN2 inhibits mTORC1 through the Rag GTPases, independently of its function as an eIF2α kinase. Later, GCN2-mediated induction of ATF4 upregulates Ddit4 followed by Sestrin2, which together cause additional mTORC1 inhibition. Additionally, we find that depletion of virtually any other amino acid also inhibits mTORC1 through GCN2. GCN2 and the dedicated amino acid sensors thus represent two independent systems that enable mTORC1 to perceive a wide spectrum of amino acids.

Keywords:  Amino Acid Sensors; Asparagine; GCN2; Glutamine; mTORC1

DOI:  https://doi.org/10.1038/s44318-025-00505-1
EMBO J. 2025 Jul 21.

Human fetal kidney organoids model early human nephrogenesis and Notch-driven cell fate.

Michael Namestnikov, Osnat Cohen-Zontag, Dorit Omer, Yehudit Gnatek, Sanja Goldberg, Thomas Vincent, Swati Singh, Yair Shiber, Tal Rafaeli Yehudai, Hadas Volkov, Dani Folkman Genet, Achia Urbach, Sylvie Polak-Charcon, Igor Grinberg, Naomi Pode-Shakked, Boaz Weisz, Zvi Vaknin, Benjamin S Freedman, Benjamin Dekel.

  Pluripotent stem cell (PSC)-derived kidney organoids are used to model human renal development and disease; however, accessible models of human fetal development to benchmark PSC-derived organoids remain underdeveloped. Here, we establish a chemically defined, serum-free protocol for prolonged culture of human fetal kidney-derived organoids (hFKOs) in vitro. hFKOs self-organize into polarized renal epithelium, reinitiate from NCAM1+ progenitors, and recapitulate nephrogenic and ureteric bud lineages. Bulk transcriptomics, single-cell RNA sequencing, pseudotime analysis, and immunostaining revealed diverse renal tissue cell populations, with a preserved epithelial progenitor pool and tubular differentiation axis. hFKOs were enriched for Notch signaling genes, enabling single-cell analysis of pharmacological Notch inhibition. This revealed a maturation block with increased nephron progenitors and a shift toward distal over early proximal tubule fates. We also identified a novel prominin-1-expressing cell state that evades Notch inhibition to generate both proximal and distal tubules. Overall, hFKOs provide a faithful model to gain insights into human kidney development, advancing the fields of stem cell biology and regenerative medicine.

Keywords:  Human Fetal Kidney; Kidney Organoids; Nephrogenesis; Notch Pathway; Single-cell Transcriptomics

DOI:  https://doi.org/10.1038/s44318-025-00504-2
Sci Rep. 2025 Jul 19. 15(1): 26217

TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency.

Wren O Nader, Kaylan S Brown, Nicholas R Boyle, Azariah K Kaplelach, Shaimaa M Abdelaziz, Skylar E Davis, Qays Aljabi, Ahmad R Hakim, Amelia G Davidson, Giacynta A Vollmer, Leah C Wright, J Bailey Echols, Joelle Saad, Nicholas S Pena, Andrew E Arrant.

  Progranulin is a pro-protein that is necessary for maintaining lysosomal function. Loss-of-function progranulin (GRN) mutations are a dominant cause of frontotemporal dementia (FTD). Brains of people with FTD due to GRN mutations accumulate lysosomal storage material and exhibit increased expression of lysosomal transcripts, which may be driven by TFEB and related transcription factors. While this may be a compensatory response to lysosomal impairment, overproduction of lysosomal proteins may also contribute to FTD pathogenesis. To investigate how TFEB may contribute to disease in people with GRN mutations, we analyzed the effects of TFEB overexpression in progranulin-insufficient cells and mice. We generated GRN knockout HEK-293 cells (GRN KO cells), which exhibited increased nuclear localization of TFEB and expression of lysosomal transcripts, but impaired autophagy. TFEB overexpression in GRN KO cells further increased lysosomal transcripts and partially normalized autophagy. We next injected an AAV vector expressing mouse Tfeb (AAV-TFEB) into the thalamus of Grn-/- mice, which accumulates lysosomal storage material. AAV-TFEB increased lysosomal transcripts and reduced immunoreactivity for SCMAS, a marker of lysosomal storage material, in Grn-/- thalamus. These data show that TFEB activity alleviates some autophagy-lysosomal deficits caused by progranulin insufficiency, suggesting potential utility of lysosome-based therapies for GRN-associated diseases.

Keywords:  Autophagy; Lysosomes; Progranulin; TFEB

DOI:  https://doi.org/10.1038/s41598-025-12268-0
Nat Commun. 2025 Jul 23. 16(1): 6792

Structural insights into cholesterol sensing by the LYCHOS-mTORC1 pathway.

Shang Yu, Jin-Hui Ding, Jia-le Wang, Weize Wang, Peng Zuo, Ao Yang, Zonglin Dai, Yuxin Yin, Jin-Peng Sun, Ling Liang.

The lysosomal cholesterol sensor LYCHOS regulates mTORC1 signaling by coupling cholesterol sensing to GATOR1-Rag GTPase modulation, yet its structural mechanisms remain unclear. Here we report six cryo-electron microscopy structures of human LYCHOS, depicting five distinct states. These are categorized into a contracted state when complexed with a sufficient amount of the cholesterol analogue cholesteryl hemisuccinate (CHS), and an expanded state when CHS is deficient. The structure forms a homodimer, within each monomer the transmembrane region is divided into a permease-like domain (PLD) and a GPCR-like domain (GLD) with two clearly defined adjacent cholesterol binding sites between them. Cholesterol binding induces a translation of GLD towards PLD and exposes the cytosolic extension of transmembrane 15, which interacts with GATOR1. Our results elucidate the structural mechanism of cholesterol sensing by the mTORC1 pathway, providing a structural basis for developing inhibitors that selectively target mTORC1 pathway by blocking LYCHOS in its expanded state.

DOI: https://doi.org/10.1038/s41467-025-61966-w
Epilepsia. 2025 Jul 24.

The transcriptomic signature of DEPDC5 KO induced mTOR hyperactivation in human neurons and its response to rapamycin treatment.

Mattson S O Jones, Silvia Lindlar, Johannes Ludwig, Regina Waltes, Afsheen Kumar, Sophie V Brauchitsch, Andrea Rossi, Evelyn Ullrich, Stefan Momma, Christine M Freitag, Jasmin K Hefendehl, Karl Martin Klein, Felix Rosenow, Denise Haslinger, Andreas G Chiocchetti.

   OBJECTIVE: Mutations of the DEP Domain Containing 5 gene (DEPDC5), a mechanistic Target of Rapamycin (mTOR) inhibitor involved in amino acid sensing, are associated with neurological diseases such as epilepsy and/or autism spectrum disorder (ASD). Loss of DEPDC5 impacts early neuronal development via mTOR hyperactivity. Although, in the mTOR-hyperactivity-associated syndrome tuberous sclerosis, mTOR inhibitors have proven to be beneficial in treating epilepsy, ASD-associated symptoms are ameliorated only partially. Similarly, the mTOR inhibitor rapamycin (RAPA) only partially rescues phenotypes induced by loss of DEPDC5 in animal models, suggesting some pathological mechanisms independent of mTOR.
METHODS: We dissected these mechanisms by identifying the DEPDC5-associated gene networks and how they are targeted by RAPA in an isogenic primary human neural progenitor (phNPC) DEPDC5 knock-out cell model.
RESULTS: We confirm that loss of DEPDC5 leads to hyperactivation of mTOR, paralleled by altered expression of mTOR-associated genes. These effects were partially (up to 33% of genes) attenuated by RAPA treatment applying a clinically comparable concentration. We did not observe an association of the differentially expressed genes with ASD or epilepsy risk genes in general. However, we identified a significant association with gene networks known to be differentially regulated in cortex samples of individuals with ASD, which were still significantly deregulated after RAPA treatment. Furthermore, genes not rescued in differentiated neurons were specifically associated with synaptic pruning and early cortical development. The observed increase in neuronal markers was confirmed morphologically. RAPA treatment recovered the increased differentiation but not the morphological changes.
SIGNIFICANCE: These new insights on the human gene network of DEPDC5 show evidence for pathological mechanisms that are not attenuated by the currently administered RAPA concentrations or that are independent of mTOR. These mechanisms should be considered as potential targets for future therapies.

Keywords:  ASD; comorbidities; epilepsy; human cell model; neural progenitor cells; transcriptomics

DOI:  https://doi.org/10.1111/epi.18549