bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2025–04–13
thirteen papers selected by
Irene Sambri, TIGEM
  1. Folliculin depletion results in liver cell damage and cholangiocarcinoma through MiT/TFE activation.
  2. STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.
  3. mTORC1 shutdown unleashes TFEB to drive triple-negative breast cancer invasion.
  4. A Gain-of-Function Mutation in Mechanistic Target of Rapamycin Results in a Tuberous Sclerosis Complex-Like Manifestation of Parenchymal Lung Disease.
  5. TFEB and TFE3 regulate STING1-dependent immune responses by controlling type I interferon signaling.
  6. Overlapping functions between Lamp2a and Lamp2b in cardiac autophagy.
  7. Foetal cardiac rhabdomyoma due to paternal TSC1 Mutation: a case report and literature review.
  8. Coordinated Regulation of Renal Glucose Reabsorption and Gluconeogenesis by mTORC2 and Potassium.
  9. Mechanistic evaluation of ertugliflozin in patients with type 2 diabetes and heart failure.
  10. Cardiovascular disease in chronic kidney disease.
  11. Intronic RNAscope probes enable precise identification of cardiomyocyte nuclei and cell cycle activity.
  12. Novel insights into kidney disease: the scRNA-seq and spatial transcriptomics approaches: a literature review.
  13. dFLASH; dual FLuorescent transcription factor activity sensor for histone integrated live-cell reporting and high-content screening.
  1. Cell Death Differ. 2025 Apr 06.
    Folliculin depletion results in liver cell damage and cholangiocarcinoma through MiT/TFE activation.
    Bruno Maria Custode, Francesco Annunziata, Felipe Dos Santos Matos, Valentina Schiano, Veronica Maffia, Milena Lillo, Rita Colonna, Rossella De Cegli, Andrea Ballabio, Nunzia Pastore.
      Mutations in the tumor suppressor gene Folliculin (FLCN) are responsible for Birt-Hogg-Dube' (BHD) syndrome, a rare inherited condition that predisposes affected individuals to skin tumors, pulmonary cysts, and kidney tumors. FLCN regulates key cellular pathways, including TFEB, TFE3, and mTORC1, which are critical for maintaining cell homeostasis. Loss of FLCN leads to both hyperactivation of mTORC1 and constitutive activation of TFEB and TFE3, contributing to tumorigenesis. While previous studies showed that Flcn liver-specific conditional knockout (FlcnLiKO) mice are protected from developing liver fibrosis and damage upon high-fat diet exposure, the potential role of FLCN loss in liver carcinogenesis remained unexplored. Here, we demonstrate that hepatic loss of FLCN in mice results in cancer associated with inflammation and fibrosis with features of cholangiocarcinoma (CCA). This phenotype emerges in mice over 90-week-old, with a male predominance. Moreover, FlcnLiKO mice are more prone to develop diethylnitrosamine (DEN)- or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- induced liver tumors with heterogenous histological features. Notably, depletion of TFE3, but not TFEB, in the liver of FlcnLiKO mice fully rescues the cancer phenotype and normalized mTORC1 signaling, highlighting TFE3 as the primary driver of liver cancer and mTORC1 hyperactivity in the absence of FLCN.
    DOI:  https://doi.org/10.1038/s41418-025-01486-8
  2. Mol Cell. 2025 Mar 27. pii: S1097-2765(25)00201-1. [Epub ahead of print]
    STING mediates lysosomal quality control and recovery through its proton channel function and TFEB activation in lysosomal storage disorders.
    Zhen Tang, Cong Xing, Antonina Araszkiewicz, Kun Yang, Wanwan Huai, Devon Jeltema, Nicole Dobbs, Yihe Zhang, Lu O Sun, Nan Yan.
      Lysosomes are essential organelles for cellular homeostasis. Defective lysosomes are associated with diseases like lysosomal storage disorders (LSDs). How lysosomal defects are detected and lysosomal function restored remain incompletely understood. Here, we show that STING mediates a neuroinflammatory gene signature in three distinct LSD mouse models, Galctwi/twi, Ppt1-/-, and Cln7-/-. Transcriptomic analysis of Galctwi/twi mouse brain tissue revealed that STING also mediates the expression of lysosomal genes that are regulated by transcriptional factor EB (TFEB). Immunohistochemical and single-nucleus RNA-sequencing (snRNA-seq) analysis show that STING regulates lysosomal gene expression in microglia. Mechanistically, we show that STING activation leads to TFEB dephosphorylation, nuclear translocation, and expression of lysosomal genes. This process requires STING's proton channel function, the V-ATPase-ATG5-ATG8 cascade, and is independent of immune signaling. Furthermore, we show that the STING-TFEB axis facilitates lysosomal repair. Together, our data identify STING-TFEB as a lysosomal quality control mechanism that responds to lysosomal dysfunction.
    Keywords:  Krabbe disease; Niemann-Pick disease; STING; TFEB; innate immunity; lysosomal storage disorder; lysosome repair; neuroinflammation; non-canonical autophagy
    DOI:  https://doi.org/10.1016/j.molcel.2025.03.008
  3. Dev Cell. 2025 Apr 07. pii: S1534-5807(25)00153-4. [Epub ahead of print]60(7): 979-981
    mTORC1 shutdown unleashes TFEB to drive triple-negative breast cancer invasion.
    Michalis Gounis, Hellyeh Hamidi, Johanna Ivaska.
      The PI3K/AKT/mTOR pathway is considered a key therapeutic target in triple-negative breast cancer (TNBC). In this issue of Developmental Cell, Remy et al. challenge this idea by demonstrating that mTORC1 inhibition activates TFEB, promoting MT1-MMP exocytosis, ECM degradation, and increased cell invasion, especially when combined with chemotherapy.
    DOI:  https://doi.org/10.1016/j.devcel.2025.03.006
  4. Chest. 2025 Apr;pii: S0012-3692(24)05460-6. [Epub ahead of print]167(4): e109-e112
    A Gain-of-Function Mutation in Mechanistic Target of Rapamycin Results in a Tuberous Sclerosis Complex-Like Manifestation of Parenchymal Lung Disease.
    Thomas C Bolig, Anjana V Yeldandi, Jane E Dematte, Anthony J Esposito.
      Dysregulation of the mechanistic target of rapamycin (mTOR) signaling pathway rarely results in parenchymal lung disease, prototypically multifocal multinodular pneumocyte hyperplasia (MMPH) and lymphangioleiomyomatosis (LAM). Although LAM can occur sporadically, to our knowledge, MMPH has not previously been described independent of tuberous sclerosis complex (TSC), a syndrome caused by germline mutations in the tumor suppressor genes TSC1 or TSC2. We report the case of a man with a history of multiple malignancies who presented with incidental chest imaging findings of innumerable ground-glass nodules and several air-filled cysts, offering a diagnostic challenge. Histopathologic findings on lung biopsy identified nodular foci of pneumocyte hyperplasia with negative Human Melanoma Black-45 staining. Next-generation DNA sequencing of the tissue showed a previously described gain-of-function mutation in MTOR. We propose that this patient's TSC-like pulmonary disease is a direct result of this mutation, a novel finding that underscores the role of Next-generation DNA sequencing in cryptic histopathology.
    Keywords:  cystic lung disease; lymphangioleiomyomatosis; mTOR; mutifocal multinodular pneumocyte hyperplasia; tuberous sclerosis complex
    DOI:  https://doi.org/10.1016/j.chest.2024.10.048
  5. Autophagy. 2025 Apr 07.
    TFEB and TFE3 regulate STING1-dependent immune responses by controlling type I interferon signaling.
    Pablo J Tapia, José A Martina, Pablo S Contreras, Akriti Prashar, Eutteum Jeong, Dominic De Nardo, Rosa Puertollano.
      STING1 is an essential component of the innate immune defense against a wide variety of pathogens. Whereas induction of type I interferon (IFN) responses is one of the best-defined functions of STING1, our transcriptomic analysis revealed IFN-independent activities of STING1 in macrophages, including transcriptional upregulation of numerous lysosomal and autophagic genes. This upregulation was mediated by the STING1-induced activation of the transcription factors TFEB and TFE3, and led to increased autophagy, lysosomal biogenesis, and lysosomal acidification. TFEB and TFE3 also modulated IFN-dependent STING1 signaling by controlling IRF3 activation. IFN production and cell death were increased in TFEB- and TFE3-depleted iBMDMs. Conversely, TFEB overexpression led to reduced IRF3 activation and an almost complete inhibition of IFN synthesis and secretion, resulting in decreased CASP3 activation and increased cell survival. Our study reveals a key role of TFEB and TFE3 as regulators of STING1-mediated innate antiviral immunity.
    Keywords:  Autophagy; STING1; TFE3; TFEB; immune response; lysosomes
    DOI:  https://doi.org/10.1080/15548627.2025.2487036
  6. Autophagy. 2025 Apr 09. 1-12
    Overlapping functions between Lamp2a and Lamp2b in cardiac autophagy.
    Marina Sampaio Cruz, Ana Maria Manso, Angel Soto-Hermida, Paul Bushway, Elizabeth Silver, Betul Beyza Gunes, Zhiyuan Tang, Giovanni Gonzalez, Sharon Lau, Jordan Arbayo, Rita H Najor, Liguo Chi, Yusu Gu, Wei Feng, Randy T Cowling, Asa B Gustafsson, Ju Chen, Eric D Adler.
      LAMP2 is a ubiquitously expressed protein critical for autophagy. Alternative splicing gives rise to three isoforms. However, the roles of major LAMP2 isoforms in the heart are not known. To address this knowledge gap, we generated lamp2a and lamp2b knockout (KO) mice to investigate the role of these isoforms in heart function and autophagy. Deletion of either Lamp2a or Lamp2b did not alter cardiac structure or function. Lack of all LAMP2 isoforms led to increased cardiac fibrosis and reduced survival during pressure overload, which were not observed in lamp2a or lamp2b KO mice. Also, LAMP2B loss did not affect levels of the autophagy markers LC3-II and SQSTM1/p62. Conversely, LAMP2A was upregulated in hearts lacking LAMP2B, potentially preserving autophagy and cardiac function. Reintroducing LAMP2A in lamp2 KO mice effectively reduced autophagosome accumulation and improved cardiac function. Overall, these data support LAMP2 isoform functional redundancy in the myocardium under pathological conditions.Abbreviations: AAV: adeno-associated virus; ACTA2: actin alpha 2, smooth muscle, aorta; CMA: chaperone-mediated autophagy; KO: knockout; LAMP2: lysosomal-associated membrane protein 2; LV: Left ventricle; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NPPA: natriuretic peptide type A; NPPB: natriuretic peptide type B; SQSTM1/p62: sequestosome 1; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; TAC: transverse aortic constriction; WT: wild type.
    Keywords:  Autophagy; LAMP2A; LAMP2B; compensatory mechanism; heart function; mouse model
    DOI:  https://doi.org/10.1080/15548627.2025.2484620
  7. Pathologica. 2025 Feb;117(1): 33-38
    Foetal cardiac rhabdomyoma due to paternal TSC1 Mutation: a case report and literature review.
    Eleonora Nardi, Angela Silvano, Oumaima Ammar, Francesca Gensini, Annabella Marozza, Lucia Pasquini, Francesca Castiglione, Viola Seravalli.
      Rhabdomyomas are the most common prenatal cardiac tumours, and are often associated with tuberous sclerosis complex (TSC). They have been shown to grow during foetal development, but may often regress or shrink in early childhood.
    In the present case, ultrasonography at 20+2 gestational weeks identified two echogenic masses suspicious of rhabdomyomas in the foetal heart. Neither of these tumours caused significant haemodynamic instability. Genetic testing of DNA extracted from amniocytes revealed a pathogenic variant of the TSC1 gene, supporting the diagnosis of tuberous sclerosis. The pregnancy was terminated at 21+1 weeks. Pathological examination confirmed the presence of two cardiac rhabdomyomas, histologically characterised by distinctive large vacuolated cells with central nuclei and radial cytoplasmic extensions.
    Further research and a multidisciplinary approach are highly recommended to improve management and outcomes of prenatal tumours.
    Keywords:  genetics; histology; rhabdomyoma,cardiac tumours; tuberous sclerosis
    DOI:  https://doi.org/10.32074/1591-951X-1099
  8. J Am Soc Nephrol. 2025 Apr 10.
    Coordinated Regulation of Renal Glucose Reabsorption and Gluconeogenesis by mTORC2 and Potassium.
    John Demko, Bidisha Saha, Enzo Takagi, Anna Mannis, Robert Weber, Hermann Koepsell, David Pearce.
       BACKGROUND: The kidney is uniquely responsible for reabsorption of filtered glucose and gluconeogenesis. Insulin stimulates glucose transport and suppresses gluconeogenesis in the proximal tubule, however, the signaling mechanisms and coordinated regulation of these processes are poorly understood. The kinase complex mTORC2 is critical for regulation of growth, metabolism, solute transport, and electrolyte homeostasis in response to a wide array of inputs. Here we examined its role in the regulation of renal glucose reabsorption and gluconeogenesis.
    METHODS: Rictor, an essential component of mTORC2, was knocked out using the Pax8-LC1 system to generate inducible tubule Rictor knockout (KO) mice. A second Rictor KO model was generated using Cre-loxP technology and a proximal tubule-specific promoter. Animals were fasted and refed on normal or high K+ diets. Metabolic parameters including glucose homeostasis and kidney function were assessed. Kidneys and livers were harvested for molecular analysis of gluconeogenic enzymes, glucose transporters, and mTORC2-regulated signaling targets.
    RESULTS: On a normal K+ diet, mTORC2 KO mice had marked glycosuria despite normal blood glucose. Immunofluorescence microscopy and immunostaining of plasma membrane protein fractions showed lower proximal tubule apical membrane SGLT2 and SGLT1 in the fed state of KO mice. Metabolic testing showed elevated fasting insulin, impaired pyruvate tolerance, and elevated hemoglobin A1c. In addition, renal gluconeogenic enzymes were increased, consistent with abnormal renal gluconeogenesis in KO mice. These effects correlated with reduced downstream phosphorylation of Akt and the transcription factor FOXO4, identifying a novel role of FOXO4 in the kidney tubules. Interestingly, high dietary K+ rapidly lowered glycosuria and gluconeogenesis, despite persistent reduction in mTORC2 substrate phosphorylation.
    CONCLUSIONS: Renal tubule mTORC2 is critical for coordinated regulation of sodium-glucose cotransporter membrane localization and renal gluconeogenesis. In the absence of mTORC2, dietary K+ promotes glucose reabsorption and suppresses gluconeogenesis independent of insulin signaling.
    DOI:  https://doi.org/10.1681/ASN.0000000703
  9. Physiol Rep. 2025 Apr;13(7): e70275
    Mechanistic evaluation of ertugliflozin in patients with type 2 diabetes and heart failure.
    Yuliya Lytvyn, Rosalie A Scholtes, Eva M Boorsma, Vikas S Sridhar, Luxcia Kugathasan, Hongyan Liu, Leif E Lovblom, Louis Handoko, Charlotte M Mosterd, John S Floras, Kevin Burns, Tosin Osuntokun, Adriaan Voors, Daniel H van Raalte, Hiddo J L Heerspink, David Z I Cherney.
      The effect of sodium-glucose cotransporter-2 (SGLT2) inhibitor ertugliflozin on fluid volume and kidney function was assessed in patients with type 2 diabetes and heart failure. Thirty-four participants were randomized in this double-blind, placebo-controlled, parallel-group, multicenter study. Physiologic measurements were obtained under clamped euglycemia at baseline, 1 week, and 12 weeks of treatment. The primary outcome was the proximal tubular natriuretic effect of ertugliflozin versus placebo, measured by fractional excretion of lithium (FELi). Ertugliflozin did not increase FELi or total FENa at 1 week or 12 weeks. Ertugliflozin increased both mean 24-h urinary sodium excretion (47.5 ± 22.1 mmol/day vs. placebo, p = 0.032) and urinary volume (p = 0.009) at 1 week, which was attenuated at Week 12. Reductions in extracellular fluid (-1.9 ± 0.8 L, p = 0.01), estimated plasma volume (-11.9 ± 13.9%, p = 0.02), and supine mean arterial pressure (-6.6 ± 2.7 mmHg, p = 0.02) were significant at Week 12. Compared to placebo, ertugliflozin acutely increased circulating angiotensinogen and angiotensin-converting enzyme (ACE) levels, as well as urine adenosine and ACE2 activity (p < 0.05). Changes in other neurohormones, sympathetic activity, kidney, and systemic hemodynamics did not differ compared to placebo. Our findings suggest that SGLT2 inhibition shifts systemic volume toward a state of euvolemia, potentially lowering the risk of worsening heart failure.
    Keywords:  SGLT2 inhibition; ertugliflozin; heart failure; type 2 diabetes
    DOI:  https://doi.org/10.14814/phy2.70275
  10. Eur Heart J. 2025 Apr 08. pii: ehaf167. [Epub ahead of print]
    Cardiovascular disease in chronic kidney disease.
    Katharina Marx-Schütt, David Z I Cherney, Joachim Jankowski, Kunihiro Matsushita, Massimo Nardone, Nikolaus Marx.
      Individuals with chronic kidney disease (CKD) exhibit an increased risk for the development of cardiovascular disease (CVD) with its manifestations coronary artery disease, stroke, heart failure, arrhythmias, and sudden cardiac death. The presence of both, CVD and CKD has a major impact on the prognosis of patients. This association likely reflects the involvement of several pathophysiological mechanisms, including shared risk factors (e.g. diabetes and hypertension), as well as other factors such as inflammation, anaemia, volume overload, and the presence of uraemic toxins. Identifying and characterizing CKD is crucial for appropriate CVD risk prediction. Mitigating CVD risk in patients with CKD mandates a multidisciplinary approach involving cardiologists, nephrologists, and other health care professionals. The present State-of-the-Art Review addresses the current understanding on the pathophysiological link between CVD and CKD, clinical implications and challenges in the treatment of these patients.
    Keywords:  CV risk; Cardiovascular disease; Chronic kidney disease; GLP-1 receptor agonists; Non-steroidal MRAs; SGLT2 inhibitors
    DOI:  https://doi.org/10.1093/eurheartj/ehaf167
  11. Commun Biol. 2025 Apr 07. 8(1): 577
    Intronic RNAscope probes enable precise identification of cardiomyocyte nuclei and cell cycle activity.
    Zhe Yu, Sen Zhang, Julius Bogomolovas, Ju Chen, Sylvia M Evans.
      Cardiac regeneration studies have been plagued by technical challenges in unequivocally identifying cardiomyocyte (CM) nuclei in cardiac sections, crucial for accurate identification of cycling CMs. The use of antibodies to sarcomeric proteins is error-prone, the CM specificity of common nuclear markers is controversial, and utilizing genetically modified mouse models poses risk of inducing unintended cardiac phenotypes. The application of RNAscope intronic probes overcomes the above shortcomings. Intronic probes label intronic RNAs within nuclei and can therefore be utilized as a method for nuclear localization. A Tnnt2 intronic RNAscope probe highly colocalized with Obscurin-H2B-GFP in adult mouse hearts, demonstrating CM specificity. Studies in embryos demonstrated that the Tnnt2 intronic RNAscope probe labeled CM nuclei that had undergone DNA replication, and remained closely associated with CM chromatin at all stages of mitosis, even with nuclear envelope breakdown. The efficiency, accuracy, and perdurance of the Tnnt2 intronic RNAscope probe even with nuclear envelope breakdown facilitated reliable investigation of dynamics of DNA synthesis and potential mitoses in CMs in both border and infarct zones after myocardial infarction (MI). Furthermore, we designed Myl2 and Myl4 intronic RNAscope probes, which labeled ventricular and atrial CM nuclei, respectively, and may help identify CM subtypes generated in vitro.
    DOI:  https://doi.org/10.1038/s42003-025-08012-z
  12. BMC Nephrol. 2025 Apr 08. 26(1): 181
    Novel insights into kidney disease: the scRNA-seq and spatial transcriptomics approaches: a literature review.
    Mingming Ma, Qiao Luo, Liangmei Chen, Fanna Liu, Lianghong Yin, Baozhang Guan.
      Over the past decade, single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have revolutionized biomedical research, particularly in understanding cellular heterogeneity in kidney diseases. This review summarizes the application and development of scRNA-seq combined with ST in the context of kidney disease. By dissecting cellular heterogeneity at an unprecedented resolution, these advanced techniques have identified novel cell subpopulations and their dynamic interactions within the renal microenvironment. The integration of scRNA-seq with ST has been instrumental in elucidating the cellular and molecular mechanisms underlying kidney development, homeostasis, and disease progression. This approach has not only identified key cellular players in renal pathophysiology but also revealed the spatial organization of cells within the kidney, which is crucial for understanding their functional specialization. This paper highlights the transformative impact of these techniques on renal research that have paved the way for targeted therapeutic interventions and personalized medicine in the management of kidney disease.
    Keywords:  Cellular heterogeneity; Kidney disease; Pathology; Renal physiology; Single-cell sequencing; Spatial transcriptomics
    DOI:  https://doi.org/10.1186/s12882-025-04103-5
  13. Nat Commun. 2025 Apr 07. 16(1): 3298
    dFLASH; dual FLuorescent transcription factor activity sensor for histone integrated live-cell reporting and high-content screening.
    Timothy P Allen, Alison E Roennfeldt, Moganalaxmi Reckdharajkumar, Adrienne E Sullivan, Miaomiao Liu, Ronald J Quinn, Darryl L Russell, Daniel J Peet, Murray L Whitelaw, David C Bersten.
      Live-cell transcription factor (TF) activity reporting is crucial for synthetic biology, drug discovery and functional genomics. Here we present dFLASH (dual FLuorescent transcription factor Activity Sensor for Histone-integrated live-cell reporting), a modular, genome-integrated TF sensor. dFLASH homogeneously and specifically detects endogenous Hypoxia Inducible Factor (HIF) and Progesterone Receptor (PGR) activities, as well as coactivator recruitment to synthetic TFs. The dFLASH system produces dual-color nuclear fluorescence, enabling normalized, dynamic, live-cell TF activity sensing with strong signal-to-noise ratios and robust screening performance (Z' = 0.61-0.74). We validate dFLASH for functional genomics and drug screening, demonstrating HIF regulation via CRISPRoff and application to whole-genome CRISPR KO screening. Additionally, we apply dFLASH for drug discovery, identifying HIF pathway modulators from a 1600-compound natural product library using high-content imaging. Together, this versatile platform provides a powerful tool for studying TF activity across diverse applications.
    DOI:  https://doi.org/10.1038/s41467-025-58488-w
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