bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2025–03–02
twelve papers selected by
Irene Sambri, TIGEM
  1. Visualization of Subcellular mTOR Complex 1 Activity with a FRET-Based Sensor (TORCAR).
  2. TFEB SUMOylation in Airway Epithelial Cells Impairs Lysosomal Biogenesis to Promote Asthma Development.
  3. Unveiling the mTOR pathway modulation by SGLT2 inhibitors: a novel approach to Alzheimer's disease in type 2 diabetes.
  4. Evolutionary conserved regulation of TFEB stability by the E3 ubiquitin ligase WWP2 modulates response to stress in vivo.
  5. Mitochondrial Dysfunction in Congenital Heart Disease.
  6. Molecular mechanisms of Hippo pathway in tumorigenesis: therapeutic implications.
  7. Kibra knockdown inhibits the aberrant Hippo pathway, suppresses renal cyst formation and ameliorates renal fibrosis in nphp1KO mice.
  8. Gut microbiota-derived metabolites: Potential targets for cardiorenal syndrome.
  9. Notch signaling pathway in osteogenesis, bone development, metabolism, and diseases.
  10. UFMylation maintains YAP stability to promote vascular endothelial cell senescence.
  11. The clinical interface of tuberous sclerosis complex and autism spectrum disorder: insights and future directions.
  12. Organoids from pluripotent stem cells and human tissues: When two cultures meet each other.
  1. Methods Mol Biol. 2025 ;2882 139-162
    Visualization of Subcellular mTOR Complex 1 Activity with a FRET-Based Sensor (TORCAR).
    Ayse Z Sahan, Sohum Metha, Jin Zhang.
      The mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient-sensing complex that integrates inputs from several pathways to promote cell growth and proliferation. mTORC1 localizes to many cellular compartments, including the nucleus, lysosomes, and plasma membrane. However, little is known about the spatial regulation of mTORC1 and the specific functions of mTORC1 at these locations. To address these questions, we previously developed a Förster resonance energy transfer (FRET)-based mTORC1 activity reporter (TORCAR) to visualize the dynamic changes in mTORC1 activity within live cells. Here, we describe a detailed protocol for using subcellularly targeted TORCAR constructs to investigate subcellular mTORC1 activities via live-cell fluorescence microscopy.
    Keywords:  Biosensor; Compartmentalized signaling; Fluorescence; Location-specific
    DOI:  https://doi.org/10.1007/978-1-0716-4284-9_7
  2. Am J Respir Cell Mol Biol. 2025 Feb 25.
    TFEB SUMOylation in Airway Epithelial Cells Impairs Lysosomal Biogenesis to Promote Asthma Development.
    Qianying Yu, Yao Zhou, Jing Wang, Meng Zhang, Caixia Di, Yujiao Wu, Qun Wu, Wen Su, Jinke Cheng, Jiajia Lv, Min Wu, Zhenwei Xia.
      Lysosomal dysfunction is the primary cause of various immune disorders. Transcription factor EB (TFEB) SUMOylation is critically involved in the lysosomal biogenesis. Whether TFEB SUMOylation-associated lysosomal dysfunction contributes to asthma pathogenesis remain to be determined. Here, we observed that ovalbumin (OVA)-stimulation impaired lysosomal function through TFEB SUMOylation, which leads to increased NLRP3 and inflammatory factors. Mechanistically, mutation of TFEB SUMOylation site did not abolish the ability of its nuclear translocation, but increased TFEB stability and binding capability with target genes' promoters, thereby promoting lysosomal biogenesis and bioactivity through liquid-liquid phase separation (LLPS), and thus inhibiting the production of inflammatory factors and alleviating allergic airway inflammation. Our observations demonstrate that TFEB SUMOylation interferes with lysosomal biogenesis contributing to asthma pathogenesis, lending mechanistic insight into asthmatic disease and improving our understanding of the transcriptional regulation of host immune responses.
    Keywords:  NLRP3 inflammasome; SUMO1; TFEB; epithelial cells; lysosomes
    DOI:  https://doi.org/10.1165/rcmb.2024-0191OC
  3. Metab Brain Dis. 2025 Feb 26. 40(3): 132
    Unveiling the mTOR pathway modulation by SGLT2 inhibitors: a novel approach to Alzheimer's disease in type 2 diabetes.
    Prakash Ramakrishan, Jayaraman Rajangam, Shaheedha Shabudeen Mahinoor, Shradha Bisht, Sabareesh Mekala, Dinesh Kumar Upadhyay, Viswas Raja Solomon, Govindaraj Sabarees, Ranakishor Pelluri.
      Alzheimer's disease (AD) is a neurological condition causing cognitive deterioration, leading to severe consequences. As the global prevalence of AD increases, new treatment approaches are needed to supplement current conventional therapies, as traditional treatments are not meeting the increasing demand for alternative treatments. It is increasingly evident that treating metabolic disorders like diabetes mellitus, obesity, and AD by blocking mechanistic target of rapamycin (mTOR) signalling is advantageous. Chronic mTOR activation may cause AD's metabolic, lysosomal, and mitochondrial dysfunction, tau hyperphosphorylation, amyloid plaque development, and disruption of the blood-brain barrier through endothelial cell malfunction. Chronic glucose loss through sodium-glucose transporter 2 (SGLT2) inhibitions can restore mTOR cycling, potentially halting or slowing AD pathogenesis. Chronic activation of mTOR is implicated in pathophysiological aspects of AD, such as metabolic dysfunction, tau hyperphosphorylation, amyloid plaque formation, and disruption of the blood-brain barrier. SGLT-2 inhibitors, commonly used in treating Type 2 Diabetes, have been shown to reduce mTOR activation and restore circadian regularity, a new finding in cognitive decline and metabolic disorders. Conversely, SGLT2 inhibitors decrease oxidative damage, inflammation, insulin signaling pathways, and proliferation of endothelial cells to enhance vascular tone, flexibility, and contractility. Along with reducing the formation of plaque containing amyloid and improving brain function, neural plasticity, acetylcholinesterase (AChE) activity, damage to the brain, and cognitive decline, they also regulate the mTOR pathway in the brain. Thus, repurposing SGLT-2 inhibitors, primarily used in diabetes treatment, presents a promising avenue for changing the way that AD is managed. The purpose of this review was to focus on the mTOR signalling cascade of SGLT 2 inhibitors to AD management in Type 2 Diabetes mellitus.
    Keywords:  Alzheimer’s disease; Diabetes mellitus; MTOR signalling futuristic therapeutics; SGLT inhibitors
    DOI:  https://doi.org/10.1007/s11011-025-01555-4
  4. iScience. 2025 Feb 21. 28(2): 111838
    Evolutionary conserved regulation of TFEB stability by the E3 ubiquitin ligase WWP2 modulates response to stress in vivo.
    Juan A Garcia-Sanchez, Estelle Bonnet, Céline Loubatier, Anne Doye, Guillaume Paillier, Fabien Segui, Frédéric Larbret, Paul Chaintreuil, Ludovic Batistic, Cédric Torre, Marcel Deckert, Jolanta Polanowska, Patrick Munro, Laurent Boyer, Orane Visvikis.
      Transcription factor EB (TFEB) is a key transcription factor that orchestrates the cellular response to stress. Dysregulation of TFEB is associated with a range of human diseases, and understanding the regulatory mechanisms of TFEB is crucial for identifying potential drug targets. In this study, we used Caenorhabditis elegans to screen for E3 ubiquitin ligases regulating the activity of TFEB's homolog, HLH-30, upon pathogenic infection. We identified WWP-1 as a regulator of HLH-30-dependent immune response controlling HLH-30 stability to mediate host defense in vivo. We found that HLH-30 interacts with WWP-1, supporting a model of WWP-1 directly regulating HLH-30. Furthermore, we found that WWP-1's human homolog WWP2 binds TFEB, directly induces TFEB ubiquitination and stabilizes TFEB. Finally, we found that WWP2 is required for TFEB-dependent host response in human monocytes-derived macrophages upon infection. Overall, our work has identified an evolutionarily conserved regulation of TFEB by WWP2 and highlighted its role in modulating stress response.
    Keywords:  Cell biology; Functional aspects of cell biology
    DOI:  https://doi.org/10.1016/j.isci.2025.111838
  5. J Cardiovasc Dev Dis. 2025 Jan 25. pii: 42. [Epub ahead of print]12(2):
    Mitochondrial Dysfunction in Congenital Heart Disease.
    Julie Pires Da Silva, Mariana Casa de Vito, Carissa Miyano, Carmen C Sucharov.
      Mitochondria play a crucial role in multiple cellular processes such as energy metabolism, generation of reactive oxygen species, excitation-contraction coupling, cell survival and death. Dysfunction of mitochondria contributes to the development of cancer; neuromuscular, cardiovascular/congenital heart disease; and metabolic diseases, including diabetes. Mitochondrial dysfunction can result in excessive reactive oxygen species, a decrease in energy production, mitophagy and apoptosis. All these processes are known to be dysregulated in cardiovascular diseases. The focus of this review is to summarize our current knowledge of mitochondrial dysfunction, including mitophagy and apoptosis, in pediatric congenital heart disease due to maternal diabetes or due to structural cardiac defects, with a focus on single-ventricle congenital heart disease. We also discuss recent mitochondria-targeted therapies for cardiovascular diseases.
    Keywords:  congenital heart disease; gestational diabetes; heterotaxy; mitochondria
    DOI:  https://doi.org/10.3390/jcdd12020042
  6. Mol Biol Rep. 2025 Feb 27. 52(1): 267
    Molecular mechanisms of Hippo pathway in tumorigenesis: therapeutic implications.
    Mohamed J Saadh, Hanan Hassan Ahmed, Radhwan Abdul Kareem, Ashok Kumar Bishoyi, R Roopashree, Debasish Shit, Renu Arya, Abhishek Sharma, Kakhramon Khaitov, Hayder Naji Sameer, Ahmed Yaseen, Zainab H Athab, Mohaned Adil.
      The Hippo signaling pathway is a pivotal regulator of tissue homeostasis, organ size, and cell proliferation. Its dysregulation is profoundly implicated in various forms of cancer, making it a highly promising target for therapeutic intervention. This review extensively evaluates the mechanisms underlying the dysregulation of the Hippo pathway in cancer cells and the molecular processes linking these alterations to tumorigenesis. Under normal physiological conditions, the Hippo pathway is a guardian, ensuring controlled cellular proliferation and programmed cell death. However, numerous mutations and epigenetic modifications can disrupt this equilibrium in cancer cells, leading to unchecked cell proliferation, enhanced survival, and metastatic capabilities. The pathway's interaction with other critical signaling networks, including Wnt/β-catenin, PI3K/Akt, TGF-β/SMAD, and EGFR pathways, further amplifies its oncogenic potential. Central to these disruptions is the activation of YAP and TAZ transcriptional coactivators, which drive the expression of genes that promote oncogenesis. This review delves into the molecular mechanisms responsible for the dysregulation of the Hippo pathway in cancer, elucidating how these disruptions contribute to tumorigenesis. We also explore potential therapeutic strategies, including inhibitors targeting YAP/TAZ activity and modulators of upstream signaling components. Despite significant advancements in understanding the Hippo pathway's role in cancer, numerous questions remain unresolved. Continued research is imperative to unravel the complex interactions within this pathway and to develop innovative and effective therapies for clinical application. In conclusion, the comprehensive understanding of the Hippo pathway's regulatory mechanisms offers significant potential for advancing cancer therapies, regenerative medicine, and treatments for chronic diseases. The translation of these insights into clinical practice will necessitate collaborative efforts from researchers, clinicians, and pharmaceutical developers to bring novel and effective therapies to patients, ultimately improving clinical outcomes and advancing the field of oncology.
    Keywords:  Cancer therapy; Hippo signaling; Regulation; TAZ; Tumorigenesis; YAP
    DOI:  https://doi.org/10.1007/s11033-025-10372-y
  7. Clin Transl Med. 2025 Mar;15(3): e70245
    Kibra knockdown inhibits the aberrant Hippo pathway, suppresses renal cyst formation and ameliorates renal fibrosis in nphp1KO mice.
    Yichen Yang, Zhihe Xue, Jiayong Lai, Jinglan Zhang, Changmiao Pang, Jinglin Zhong, Zhanpeng Kuang, Baojuan Zou, Yaqing Liu, Liangzhong Sun.
       INTRODUCTION: Nephronophthisis (NPH) is an autosomal recessive interstitial cystic kidney disease, which is the most common genetic cause of end-stage renal disease (ESRD) in childhood. The Hippo pathway is regulated by the cilium and has been suggested to be linked to NPH. The aim of the study was to investigate the involvement of Hippo pathway in the pathogenesis of nphp1 defect-associated NPH (NPH1).
    METHOD: Nphp1 knockout (nphp1KO) Madin-Darby Canine Kidney (MDCK) cells and nphp1KO C57BL/6J mice were generated via CRISPR gene editing strategy. The siRNAs targeting Kibra, MST1 and LATS1 were designed. An AAV9 vector was designed for Kibra knockdown. The expression and phosphorylation of core Hippo pathway molecules were evaluated. Pathological renal changes were evaluated via light microscopy respectively with haematoxylin-eosin and Masson staining.
    RESULTS: In nphp1KO MDCK cells, nphp1KO mice and NPH1 patients' kidneys, Kibra, p-MST1/2, p-LATS and p-YAP exhibited a notable increase in levels, with an even greater elevation observed in renal cyst cells, indicating the Hippo pathway activated in these nphp1-deficient contexts. Nphp1 re-expression reversed the Hippo pathway activation in cells, indicating that the Hippo pathway activation is related to nphp1 deficiency in vitro. Meanwhile, in vitro, MST1 knockdown downregulated LATS1 and YAP phosphorylation, LATS1 knockdown downregulated YAP phosphorylation, suggesting the activation of the canonical Hippo pathway in nphp1-deficient contexts. Knockdown of the upstream regulator Kibra inhibited the Hippo pathway activation in both nphp1KO MDCK cells and mice. Following Kibra knockdown, the organisation of nphp1KO MDCK cells became more compact, the intensity of the actin fibres increased. Besides, decreased renal fibrosis and cyst formation were observed in nphp1KO mice.
    CONCLUSIONS: The canonical Hippo pathway is aberrantly activated in nphp1-deficient conditions. Kibra may serve as a crucial upstream regulator of nphp1 deficiency-related Hippo pathway activation. Kibra upregulation and activation of the Hippo pathway are involved in the pathogenesis of NPH1.
    KEY POINTS: Canonical Hippo pathway activated in nphp1-deficient disease models and patients. Kibra was a key upstream molecule in regulating the activation of canonical Hippo pathway in nphp1-deficient disease models and patients and closely related to renal cyst formation and fibrosis in nphp1KO mice.
    Keywords:  Hippo pathway; Kibra; nephronophthisis; nphp1; renal cyst
    DOI:  https://doi.org/10.1002/ctm2.70245
  8. Pharmacol Res. 2025 Feb 24. pii: S1043-6618(25)00097-0. [Epub ahead of print] 107672
    Gut microbiota-derived metabolites: Potential targets for cardiorenal syndrome.
    Yuchen Lai, Yujie Zhu, Xihui Zhang, Shifang Ding, Fang Wang, Jincen Hao, Zhaomeng Wang, Congqi Shi, Yongjin Xu, Lemin Zheng, Wei Huang.
      The characteristic of cardiorenal syndrome (CRS) is simultaneous damage to both the heart and kidneys. CRS has caused a heavy burden of mortality and incidence rates worldwide. The regulation of host microbiota metabolism that triggers heart and kidney damage is an emerging research field that promotes a new perspective on cardiovascular risk. We summarize current studies from bench to bedside of gut microbiota-derived metabolites to better understand CRS in the context of gut microbiota-derived metabolites. We focused on the involvement of gut microbiota-derived metabolites in the pathophysiology of CRS, including lipid and cholesterol metabolism disorders, coagulation abnormalities and platelet aggregation, oxidative stress, endothelial dysfunction, inflammation, mitochondrial damage and energy metabolism disorders, vascular calcification and renal fibrosis, as well as emerging therapeutic approaches targeting CRS metabolism in gut microbiota-derived metabolites which provides an innovative treatment approach for CRS to improve patient prognosis and overall quality of life.
    Keywords:  Cardiorenal syndrome; Gut microbiota-derived metabolites; Heart failure; Renal insufficiency
    DOI:  https://doi.org/10.1016/j.phrs.2025.107672
  9. FASEB J. 2025 Feb 28. 39(4): e70417
    Notch signaling pathway in osteogenesis, bone development, metabolism, and diseases.
    Muhammad Dilawar, Xuan Yu, Yuanyuan Jin, Jing Yang, Sisi Lin, Junguang Liao, Qi Dai, Xingen Zhang, Muhammad Farrukh Nisar, Guiqian Chen.
      The skeletal system provides vital importance to support organ development and functions. The Notch signaling pathway possesses well-established functions in organ development and cellular homeostasis. The Notch signaling pathway comprises five typical ligands (JAG1, JAG2, DLL1, DLL3, and DLL4), four receptors (Notch1-4), and four intracellular domains (NICD1-4). Each component of the Notch signaling pathway has been demonstrated to be fundamental in osteoblast differentiation and bone formation. The dysregulation in the Notch signaling pathway is highly linked with skeletal disorders or diseases at the developmental and postnatal stages. Recent studies have highlighted the importance of the elements of the Notch signaling pathway in the skeletal system, as well as its interaction with signaling, such as Wnt/β-catenin, BMP, TGF-β, FGF, autophagy, and hedgehog (Hh) to construct a potential gene regulatory network to orchestrate osteogenesis and ossification. Our review has provided a comprehensive summary of the Notch signaling pathway in the skeletal system, as well as the insights targeting Notch signaling for innovative potential drug discovery targets or therapeutic interventions to treat bone disorders, such as osteoporosis and osteoarthritis. An in-depth molecular mechanistic strategy to modulate the Notch signaling pathway and its associated signaling pathway will be encouraged for consideration to trigger enhanced therapeutic approaches for bone disorders by defining Notch-regulating drugs for clinical use.
    Keywords:  Notch signal pathway; bone formation; osteoarthritis; osteoblast differentiation; osteoporosis
    DOI:  https://doi.org/10.1096/fj.202402545R
  10. iScience. 2025 Feb 21. 28(2): 111854
    UFMylation maintains YAP stability to promote vascular endothelial cell senescence.
    Yanan Liu, Min Zuo, Aiwei Wu, Zhaoxiang Wang, Siting Wang, Yongping Bai, Junzhi Zhou, Hu Wang.
      Endothelial cell (EC) senescence is an accomplice for vascular aging, which leads to cardiovascular diseases (CVDs). Evidences showed that Hippo-Yes-associated protein (YAP) signaling pathway plays an essential role in aging-associated CVDs. Here, we reported that YAP was elevated in senescent human umbilical vein endothelial cells (HUVECs) and inhibition of YAP could attenuate HUVECs senescence. Besides, our findings revealed that the activity of UFMylation and the level of YAP were both elevated in senescent cells. Furthermore, UFM1-modified YAP was upregulated in senescent ECs, and increased the stability of YAP. Importantly, we found that compound 8.5, an inhibitor of E1 of UFMylation, can alleviate vascular aging in aged mice. Together, our finding provides molecular mechanism by which UFMylation maintains YAP stability and exerts an important role in promoting cell senescence, and identified that a previously unrecognized UFMylation is a potential therapeutic target for anti-aging.
    Keywords:  Biochemistry; Biological sciences; Cell; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2025.111854
  11. Neurol Sci. 2025 Feb 25.
    The clinical interface of tuberous sclerosis complex and autism spectrum disorder: insights and future directions.
    Reet Ramani, Barika Fatima, Abuzar Hussain, Umer Shahid, Aman Kamani, Sahibzada Mohammad Abu Bakar, Hufsa Naveed, Tooba Naveed, Saba Ambreen Aftab, Ahmed Zubair Abbasi.
       BACKGROUND AND OBJECTIVE: Tuberous sclerosis complex (TSC) is a hereditary disorder that leads to tumor growth in various organs. Manifestations from mutations in the TSC1 or TSC2 genes comprise seizures, developmental delay, and skin abnormalities. This literature search has been dedicated to emphasizing the critical role of early diagnosis and the formulation of individualized plans for this target population with co-occurring TSC and Autism Spectrum Disorder (ASD).
    EXPERIMENTAL PROCEDURE: Behavioral and developmental tests can evaluate ASD symptoms; neuroimaging methods like functional MRI and PET scans can identify brain abnormalities, and molecular genetic analysis can detect TSC1/TSC2 mutations. Differential Diagnostic Approach These include medical histories and physical examinations to consider that ASD and TSC present the same symptoms.
    RESULTS: Although 90% of TSC patients are reported to have TSC-associated neuropsychiatric disorders, 30-50% of patients fulfil the clinical criteria of ASD. In comparison, the estimate for the rate of ASD prevalence in TSC patients ranges from 17 to 63%, with the characteristics of infantile spasms and early-onset epilepsy. The diagnosis is further challenged by the fact that there are shared symptoms between both, namely seizures and intellectual impairment.
    CONCLUSION: The shared symptoms between TSC and ASD suggest the need for multidisciplinary approaches in both diagnosis and treatment. A personalized therapeutic plan should include behavioral therapy, medication with Everolimus, mammalian target of rapamycin (mTOR) inhibitors, and advanced neuroimaging. The future of research in biomarkers, molecular medicines, and improving diagnostic protocols holds great promise for optimizing patient care and treatment options.
    Keywords:  Autism spectrum disorder; TSC1/TSC2; Tuberous sclerosis complex; Tuberous sclerosis complex-associated neuropsychiatric disorders
    DOI:  https://doi.org/10.1007/s10072-025-08065-2
  12. Dev Cell. 2025 Feb 24. pii: S1534-5807(25)00005-X. [Epub ahead of print]60(4): 493-511
    Organoids from pluripotent stem cells and human tissues: When two cultures meet each other.
    Benedetta Artegiani, Delilah Hendriks.
      Human organoids are a widely used tool in cell biology to study homeostatic processes, disease, and development. The term organoids covers a plethora of model systems from different cellular origins that each have unique features and applications but bring their own challenges. This review discusses the basic principles underlying organoids generated from pluripotent stem cells (PSCs) as well as those derived from tissue stem cells (TSCs). We consider how well PSC- and TSC-organoids mimic the different intended organs in terms of cellular complexity, maturity, functionality, and the ongoing efforts to constitute predictive complex models of in vivo situations. We discuss the advantages and limitations associated with each system to answer different biological questions including in the field of cancer and developmental biology, and with respect to implementing emerging advanced technologies, such as (spatial) -omics analyses, CRISPR screens, and high-content imaging screens. We postulate how the two fields may move forward together, integrating advantages of one to the other.
    Keywords:  CRISPR; adult; cancer; co-culture; development; fetal; imaging; organoids; pluripotent stem cells; tissue stem cells
    DOI:  https://doi.org/10.1016/j.devcel.2025.01.005
This page is being maintained by Thomas Krichel. It was last updated on 2025‒03‒02 at 8:59.