bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2025–03–30
ten papers selected by
Irene Sambri, TIGEM
  1. Tuberous Sclerosis Complex: New Insights into Pathogenesis and Therapeutic Breakthroughs.
  2. Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate.
  3. Antagonistic roles for MITF and TFE3 in melanoma plasticity.
  4. The Hippo pathway: Organ size control and beyond.
  5. The Rab3 GTPase Cycle Modulates Cardiomyocyte Exocytosis and Atrial Natriuretic Peptide Release.
  6. The Hippo pathway effector YAP inhibits NF-κB signaling and ccRCC growth by opposing ZHX2.
  7. Lysosomal PIP3 revealed by genetically encoded lipid biosensors.
  8. The metabolic sensor LKB1 regulates ILC3 homeostasis and mitochondrial function.
  9. Retinal gene therapy for Stargardt disease with dual AAV intein vectors is both safe and effective in large animal models.
  10. TFE3 fusions drive oxidative metabolism and ferroptosis resistance in translocation renal cell carcinoma.
  1. Life (Basel). 2025 Feb 26. pii: 368. [Epub ahead of print]15(3):
    Tuberous Sclerosis Complex: New Insights into Pathogenesis and Therapeutic Breakthroughs.
    Aurora Alexandra Jurca, Alexandru Daniel Jurca, Codruta Diana Petchesi, Dan Bembea, Claudia Maria Jurca, Emilia Severin, Sanziana Jurca, Cosmin Mihai Vesa.
      Background/Objectives: Tuberous sclerosis complex (TSC) is a rare, autosomal dominant genetic disorder caused by mutations in the TSC1 and TSC2 genes, which disrupt the regulation of the mammalian target of rapamycin (mTOR) pathway, a critical regulator of cellular growth. The disorder presents as a multisystem condition, with benign tumors (hamartomas) developing in organs such as the brain, skin, heart, kidneys, and lungs, leading to significant clinical variability and impact on quality of life. This review aims to summarize recent advances in the understanding of TSC pathogenesis and clinical variability and evaluate the therapeutic breakthroughs in targeted treatments. Methods: A narrative review was conducted using various available databases. We applied objective evaluation metrics, such as the impact factor of the journals and the citation count, to assess the quality of the studies. Results: Targeted therapies, particularly mTOR inhibitors (mTORis), have shown efficacy in reducing hamartoma size, improving neuropsychiatric symptoms, and enhancing patient outcomes. Despite these advances, variability in disease expression poses challenges in diagnosis and individualized management strategies. Conclusions: Challenges such as early diagnosis, optimizing long-term outcomes, and addressing residual unmet needs remain critical. Future research should prioritize precision medicine approaches and patient-centered care models within centers of expertise to improve treatment efficacy and quality of life for individuals with TSC.
    Keywords:  TSC1 gene; TSC2 gene; hamartomas; mTOR inhibitors
    DOI:  https://doi.org/10.3390/life15030368
  2. Nat Commun. 2025 Mar 21. 16(1): 2815
    Structural basis for cholesterol sensing of LYCHOS and its interaction with indoxyl sulfate.
    Zhenhua Wang, Jingjing He, Yufan Yang, Yonglin He, Hongwu Qian.
      The lysosome serves as an essential nutrient-sensing hub within the cell, where the mechanistic target of rapamycin complex 1 (mTORC1) is activated. Lysosomal cholesterol signaling (LYCHOS), a lysosome membrane protein, has been identified as a cholesterol sensor that couples cholesterol concentration to mTORC1 activation. However, the molecular basis is unknown. Here, we determine the cryo-electron microscopy (cryo-EM) structure of human LYCHOS at a resolution of 3.1 Å, revealing a cholesterol-like density at the interface between the permease and G-protein coupled receptor (GPCR) domains. Advanced 3D classification reveals two distinct states of LYCHOS. Comparative structural analysis between these two states demonstrated a cholesterol-related movement of GPCR domain relative to permease domain, providing structural insights into how LYCHOS senses lysosomal cholesterol levels. Additionally, we identify indoxyl sulfate (IS) as a binding ligand to the permease domain, confirmed by the LYCHOS-IS complex structure. Overall, our study provides a foundation and indicates additional directions for further investigation of the essential role of LYCHOS in the mTORC1 signaling pathway.
    DOI:  https://doi.org/10.1038/s41467-025-58087-9
  3. Cell Rep. 2025 Mar 25. pii: S2211-1247(25)00245-1. [Epub ahead of print]44(4): 115474
    Antagonistic roles for MITF and TFE3 in melanoma plasticity.
    Jeremy Chang, Katelyn R Campbell-Hanson, Marion Vanneste, Nicholas I Bartschat, Ryan Nagel, Asdis K Arnadottir, Hong Nhung Vu, Collin Montgomery, Julius Yevdash, Jiarui Jiang, Ardith Bhinu, Annika Helverson, Michael D Henry, Eiríkur Steingrímsson, Ronald J Weigel, Robert A Cornell, Colin Kenny.
      Melanoma cells can switch from a melanocytic and proliferative state to a mesenchymal and invasive state and back again. This plasticity drives intratumoral heterogeneity, progression, and therapeutic resistance. Microphthalmia-associated transcription factor (MITF) promotes the melanocytic/proliferative phenotype, but factors that drive the mesenchymal/invasive phenotype and the mechanisms that effect the switch between cell states are unclear. Here, we identify the MITF paralog, TFE3, and the non-canonical mTORC1 pathway as regulators of the mesenchymal state. We show that TFE3 expression drives the metastatic phenotype in melanoma cell lines and tumors. Deletion of TFE3 in MITF-low melanoma cell lines suppresses their ability to migrate and metastasize. Further, MITF suppresses the mesenchymal phenotype by directly or indirectly activating expression of FNIP1, FNIP2, and FLCN, which encode components of the non-canonical mTORC1 pathway, thereby promoting cytoplasmic retention and lysosome-mediated degradation of TFE3. These findings highlight a molecular pathway controlling melanoma plasticity and invasiveness.
    Keywords:  CP: Cancer; CP: Genomics; MITF; TFE3; cell plasticity; mTORC1; melanoma; metastasis; phenotype switching; protein stability
    DOI:  https://doi.org/10.1016/j.celrep.2025.115474
  4. Pharmacol Rev. 2025 Mar;pii: S0031-6997(24)12631-2. [Epub ahead of print]77(2): 100031
    The Hippo pathway: Organ size control and beyond.
    Pengfei Guo, Sicheng Wan, Kun-Liang Guan.
      The Hippo signaling pathway is a highly conserved signaling network for controlling organ size, tissue homeostasis, and regeneration. It integrates a wide range of intracellular and extracellular signals, such as cellular energy status, cell density, hormonal signals, and mechanical cues, to modulate the activity of YAP/TAZ transcriptional coactivators. A key aspect of Hippo pathway regulation involves its spatial organization at the plasma membrane, where upstream regulators localize to specific membrane subdomains to regulate the assembly and activation of the pathway components. This spatial organization is critical for the precise control of Hippo signaling, as it dictates the dynamic interactions between pathway components and their regulators. Recent studies have also uncovered the role of biomolecular condensation in regulating Hippo signaling, adding complexity to its control mechanisms. Dysregulation of the Hippo pathway is implicated in various pathological conditions, particularly cancer, where alterations in YAP/TAZ activity contribute to tumorigenesis and drug resistance. Therapeutic strategies targeting the Hippo pathway have shown promise in both cancer treatment, by inhibiting YAP/TAZ signaling, and regenerative medicine, by enhancing YAP/TAZ activity to promote tissue repair. The development of small molecule inhibitors targeting the YAP-TEAD interaction and other upstream regulators offers new avenues for therapeutic intervention. SIGNIFICANCE STATEMENT: The Hippo signaling pathway is a key regulator of organ size, tissue homeostasis, and regeneration, with its dysregulation linked to diseases such as cancer. Understanding this pathway opens new possibilities for therapeutic approaches in regenerative medicine and oncology, with the potential to translate basic research into improved clinical outcomes.
    DOI:  https://doi.org/10.1016/j.pharmr.2024.100031
  5. Biophys J. 2025 Mar 20. pii: S0006-3495(25)00167-5. [Epub ahead of print]
    The Rab3 GTPase Cycle Modulates Cardiomyocyte Exocytosis and Atrial Natriuretic Peptide Release.
    Kobina Essandoh, Arasakumar Subramani, Sribharat Koripella, Matthew J Brody.
      Natriuretic peptides are produced predominantly by atrial cardiomyocytes in response to cardiovascular stress and attenuate cardiac maladaptation by reducing blood pressure, blood volume, and cardiac workload primarily through activation of natriuretic peptide receptors in the kidney and vasculature. However, mechanisms underlying cardiomyocyte exocytosis and natriuretic peptide secretion remain poorly defined. Manipulation of Rab3a GTPase activity by Rab3gap1 was recently found to modulate atrial natriuretic peptide (ANP) release by cardiomyocytes. Here, we examined upstream signaling mechanisms and the role of the Rab3a GTPase cycle in exocytosis and ANP secretion by cardiomyocytes. Pharmacological inhibition of the heterotrimeric G protein subunit G⍺q suppressed ANP secretion at baseline and prevented GTP-loading of Rab3a and ANP release in neonatal rat cardiomyocytes (NRCMs) in response to phenylephrine (PE). Similar to agonist-induced activation of ANP secretion, genetic overexpression of a constitutively-active, GTP-loaded Rab3a mutant (Q81L) in NRCMs resulted in enhanced intracellular distribution of Rab3a at endomembranes peripheral to the Golgi and promotion of ANP release, indicating that enhancement of Rab3a activity is sufficient to elicit ANP secretion by cardiomyocytes. Collectively, these data indicate G⍺q signaling downstream of receptor activation and Rab3a-regulated secretory pathway activity and exocytosis facilitate ANP release by cardiomyocytes that could potentially be harnessed to antagonize hypertension and adverse cardiac remodeling in cardiovascular disease.
    DOI:  https://doi.org/10.1016/j.bpj.2025.03.013
  6. J Biol Chem. 2025 Mar 20. pii: S0021-9258(25)00279-0. [Epub ahead of print] 108430
    The Hippo pathway effector YAP inhibits NF-κB signaling and ccRCC growth by opposing ZHX2.
    Xu Li, Yong Suk Cho, Yuhong Han, Mengmeng Zhou, Yuchen Liu, Yingzi Yang, Shu Zhuo, Jin Jiang.
      The prevailing view in the cancer field is that Hippo signaling pathway functions as a tumor suppressor pathway by blocking the oncogenic potential of the pathway effectors Yes1 associated transcriptional regulator (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ). However, YAP can also function as a context-dependent tumor suppressor in several types of cancer including clear cell renal cell carcinomas (ccRCC). We find that, in additional to inhibiting hypoxia-inducible factor 2α (HIF2α), a major oncogenic driver in Von Hippel-Lindau (VHL)-/- ccRCC, YAP also blocks nuclear factor κB (NF-κB) signaling in ccRCC to inhibit cancer cell growth under conditions where HIF2α is dispensable. Mechanistically, YAP inhibits the expression of Zinc fingers and homeoboxes 2 (ZHX2), a VHL substrate and critical co-factor of NF-κB in ccRCC. Furthermore, YAP competes with ZHX2 for binding to the NF-κB subunit p65. Consequently, elevated nuclear YAP blocks the cooperativity between ZHX2 and the NF-κB subunit p65, leading to diminished NF-κB target gene expression. Pharmacological inhibition of Hippo kinase blocked NF-κB transcriptional program and suppressed ccRCC cancer cell growth, which can be rescued by overexpression of ZHX2 or p65. Our study uncovers a crosstalk between the Hippo and NF-κB/ZHX2 pathways and its involvement in ccRCC growth inhibition, suggesting that targeting the Hippo pathway may provide a therapeutical opportunity for ccRCC treatment.
    Keywords:  Hippo; NF-κB; TEAD; YAP; ZHX2; cancer; ccRCC; p65
    DOI:  https://doi.org/10.1016/j.jbc.2025.108430
  7. Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2426929122
    Lysosomal PIP3 revealed by genetically encoded lipid biosensors.
    Ayse Z Sahan, Mingyuan Chen, Qi Su, Qingrong Li, Dong Wang, Jin Zhang.
      3-Phosphoinositides (3-PIs), phosphatidylinositol (3,4) bisphosphate [PI(3,4)P2] and phosphatidylinositol (3,4,5) trisphosphate (PIP3), are important lipid second messengers in the Phosphoinositide 3-Kinase (PI3K)/Akt signaling pathway, which is crucial to cell growth and frequently dysregulated in cancer. Emerging evidence suggests these lipid second messengers may be present in membranes beyond the plasma membrane, yet their spatial regulation within other membrane compartments is not well understood. To dissect the spatial regulation of specific 3-PI species, we developed genetically encodable biosensors with selectivity for PIP3 or PI(3,4)P2. Using these biosensors, we showed that PIP3 significantly accumulated at the lysosome upon growth factor stimulation, in contrast to the conventional view that PIP3 is exclusively present in the plasma membrane. Furthermore, we showed that lysosomal PIP3 originates from the plasma membrane and relies on dynamin-dependent endocytosis for lipid internalization. Thus, PIP3 can exploit dynamic trafficking pathways to access subcellular compartments and regulate signaling in a spatially selective manner.
    Keywords:  3-phosphoinositide; cellular signaling; fluorescent biosensor; lysosome; spatiotemporal regulation
    DOI:  https://doi.org/10.1073/pnas.2426929122
  8. Cell Rep. 2025 Mar 21. pii: S2211-1247(25)00227-X. [Epub ahead of print]44(4): 115456
    The metabolic sensor LKB1 regulates ILC3 homeostasis and mitochondrial function.
    Diogo Fonseca-Pereira, Sena Bae, Slater L Clay, Monia Michaud, Meghan H MacDonald, Jonathan N Glickman, Wendy S Garrett.
      Group 3 innate lymphoid cells (ILC3s) are tissue-resident cells that sense environmental cues, control infections, and promote tissue homeostasis at mucosal surfaces. The metabolic sensor liver kinase B1 (LKB1) integrates intracellular stress, metabolism, and mitochondrial function to promote the development and effector functions of a variety of immune cells; however, the role of LKB1 in ILC3 function was unknown. Here, we show that LKB1 is crucial for adult ILC3 homeostasis, cytokine production, and mitochondrial function. ILC3-specific LKB1 deletion resulted in a reduced number of ILC3s and interleukin-22 (IL-22) production. LKB1-deficient ILC3s had decreased survival, mitochondrial dysfunction, cytoplasmic lipid accumulation, and altered bioenergetics. Using LKB1 downstream kinase modulators, we found that LKB1 regulation of ILC3 survival and IL-22 production requires signaling through microtubule affinity-regulating kinases (MARKs). Mechanistically, LKB1 deficiency resulted in increased reactive oxygen species (ROS) production and NFAT2 and PD-1 expression. Our work reveals that metabolic regulation of enteric ILC3 function by an LKB1-dependent signaling network is crucial for intestinal immunity and tissue homeostasis.
    Keywords:  CP: Immunology; CP: Metabolism; ILC3; LKB1; group 3 innate lymphoid cells; liver kinase B1; mitochondrial function
    DOI:  https://doi.org/10.1016/j.celrep.2025.115456
  9. Sci Adv. 2025 Mar 28. 11(13): eadt9354
    Retinal gene therapy for Stargardt disease with dual AAV intein vectors is both safe and effective in large animal models.
    Rita Ferla, Eugenio Pugni, Mariangela Lupo, Paola Tiberi, Federica Fioretto, Andrea Perota, Roberto Duchi, Irina Lagutina, Carlo Gesualdo, Settimio Rossi, Domenico Ventrella, Alberto Elmi, Benjamin McClinton, Carmel Toomes, Tongzhou Xu, Robert S Molday, Enrico M Surace, Francesca Simonelli, Maria L Bacci, Cesare Galli, Muhammad A Memon, Naveed Shams, Alberto Auricchio, Ivana Trapani.
      Retinal gene therapy using dual adeno-associated viral (AAV) intein vectors can be applied to genetic forms of blindness caused by mutations in genes with coding sequences that exceed single AAV cargo capacity, such as Stargardt disease (STGD1), the most common inherited macular dystrophy. In view of clinical translation of dual AAV intein vectors, here we set to evaluate both the efficiency and safety of their subretinal administration in relevant large animal models. Accordingly, we have developed the first pig model of STGD1, which we found to accumulate lipofuscin similarly to patients. This accumulation is significantly reduced upon subretinal administration of dual AAV intein vectors whose safety and pharmacodynamics we then tested in nonhuman primates, which showed modest and reversible inflammation as well as high levels of photoreceptor transduction. This bodes well for further clinical translation of dual AAV intein vectors in patients with STGD1 as well as for other blinding diseases that require the delivery of large genes.
    DOI:  https://doi.org/10.1126/sciadv.adt9354
  10. EMBO Mol Med. 2025 Mar 27.
    TFE3 fusions drive oxidative metabolism and ferroptosis resistance in translocation renal cell carcinoma.
    Alexandra Helleux, Guillaume Davidson, Antonin Lallement, Fatima Al Hourani, Alexandre Haller, Isabelle Michel, Anas Fadloun, Christelle Thibault-Carpentier, Xiaoping Su, Véronique Lindner, Thibault Tricard, Hervé Lang, Nizar M Tannir, Irwin Davidson, Gabriel G Malouf.
      The oncogenic mechanisms by which TFE3 fusion proteins drive translocation renal cell carcinoma (tRCC) are poorly characterized. Here, we integrated loss and gain of function experiments with multi-omics analyses in tRCC cell lines and patient tumors. High nuclear accumulation of NONO-TFE3 or PRCC-TFE3 fusion proteins promotes their broad binding across the genome at H3K27ac-marked active chromatin, engaging a core set of M/E-box-containing regulatory elements to activate specific gene expression programs as well as promiscuous binding to active promoters to stimulate mRNA synthesis. Within the core program, TFE3 fusions directly regulate genes involved in ferroptosis resistance and oxidative phosphorylation metabolism (OxPhos). Consequently, human tRCC tumors display high OxPhos scores that persist during their epithelial to mesenchymal transition (EMT). We further show that tRCC tumor aggressiveness is related to their EMT and their associated enrichment in myofibroblast cancer-associated fibroblasts (myCAFs) that are both hallmarks of poor prognostic outcomes. We define tRCC as a novel metabolic subtype of renal cancer and provide unique insights into how broad genomic binding of TFE3 fusion proteins regulates OxPhos and ferroptosis resistance.
    Keywords:  Cancer Associated Fibroblasts; Ferroptosis; Metabolism; RNA Synthesis; TFE3
    DOI:  https://doi.org/10.1038/s44321-025-00221-7
This page is being maintained by Thomas Krichel. It was last updated on 2025‒03‒30 at 16:41.