bims-raghud 2026-10-25 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2026–10–25
ten papers selected by
Irene Sambri, TIGEM

cAMP signaling promotes acute lysosome biogenesis through TFEB nuclear import-export dynamics.
Hyperosmotic stress in renal tubular epithelial cells promotes TFEB-dependent autophagy in interstitial fibroblasts by involving extracellular glutamate.
Birt-Hogg-Dubé syndrome.
Metformin improves mitophagy-related pathways and mitochondrial-lysosomal homeostasis in chromosome 21 trisomic fibroblasts.
Loss of intestinal Akt elicits rapid mortality via intestinal damage which is rescued by mTORC1 activation.
Polycystin dysfunction and cardiac electrical abnormalities in ADPKD.
AMPK signaling in cancer: Molecular insights and therapeutic opportunities.
Repressed mTORC1 signaling and transient dendritic pruning support axonal regeneration in adult zebrafish.
TGF-β in chronic kidney disease: a controversy for decades.
The Lysosomal Clock: Are We Only as Old as Our Lysosomes?

J Cell Sci. 2026 Oct 20. pii: jcs.264721. [Epub ahead of print]

cAMP signaling promotes acute lysosome biogenesis through TFEB nuclear import-export dynamics.

Saumya Bhatt, Mohammad Ali Abbas Zaidi, Hadley R Taggart, Nicholas Woods, Yiyang Wu, Subramanian P Ramanathan, Cody N Rozeveld, Micah B Schott.

  Cyclic adenosine monophosphate (cAMP) signaling is a major stimulus for lipid and glucose catabolism, yet catabolic processes like these can also coordinate with lysosome-dependent degradation. However, the impact of cAMP signaling on lysosomal dynamics remains unclear. Transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, is regulated by stimulus-dependent nuclear-cytoplasmic shuttling through a variety of phosphorylation events. Here, we find that elevating intracellular cAMP with forskolin and IBMX induces rapid nuclear import of TFEB-GFP within 30 minutes and coincides with a transient upregulation of TFEB target lysosome genes. By 8 hours, TFEB returns to the cytoplasm, accompanied by transcriptional downregulation. Inhibition of cAMP-dependent protein kinase A (PKA) using H89 did not block nuclear import but unexpectedly caused sustained nuclear accumulation, indicating that PKA promotes TFEB nuclear export. Consistent with this, phosphoproteomic profiling revealed increased phosphorylation of a PKA-consensus motif (RRxS) during the export phase. These findings suggest that cAMP-PKA signaling plays a novel role in temporally "tuning" lysosomal gene expression by regulating TFEB nuclear-cytoplasmic shuttling.

Keywords:  Lysosome; Nuclear Export; Nuclear import; Protein Kinase A; Transcription Factor EB; cAMP

DOI:  https://doi.org/10.1242/jcs.264721
Biochim Biophys Acta Mol Cell Res. 2026 Oct 20. pii: S0167-4889(26)00137-0. [Epub ahead of print]1874(1): 120238

Hyperosmotic stress in renal tubular epithelial cells promotes TFEB-dependent autophagy in interstitial fibroblasts by involving extracellular glutamate.

Takashi Miyano, Yoshikazu Yamagishi, Naoya Sakamoto, Toshihiro Sera.

  Renal tubular epithelial-interstitial fibroblast communication maintains kidney homeostasis but promotes disease when dysregulated. Tubular epithelial cells undergo large physiological osmotic fluctuations; however, it remains unclear whether epithelial hyperosmotic stress sends signals to neighboring fibroblasts. Herein, we examined how epithelial hyperosmotic stress regulates fibroblast autophagy and transcription factor EB (TFEB) activity. We used a Transwell co-culture system with rat proximal tubular epithelial cells (NRK-52E) and renal interstitial fibroblasts (NRK-49F), which allowed evaluation of the paracrine effect on fibroblasts mediated by tubular epithelial cells. Hyperosmotic stress in epithelial cells induced the robust nuclear translocation of TFEB in fibroblasts, increased the expression of lysosomal and autophagy-related genes, and enhanced autophagic flux without altering fibroblast viability or proliferation. Although fibroblasts internalized epithelial-derived extracellular vesicles, they did not activate TFEB, suggesting an extracellular vesicles-independent mechanism. RNA sequencing revealed that hyperosmotic stress markedly alters the expression of epithelial solute carrier genes, particularly those encoding amino acid transporters. Analysis of amino acid metabolism revealed corresponding changes in conditioned media, including an increase in extracellular glutamate. Glutamate alone induced TFEB nuclear translocation and autophagy activation in fibroblasts. Both epithelial hyperosmotic co-culture and glutamate treatment activated AMP-activated protein kinase and inhibited mTORC1 signaling, thereby enabling TFEB activation. These results identify extracellular glutamate as a metabolite-based paracrine signal that couples epithelial osmotic stress with TFEB-dependent autophagy in interstitial fibroblasts.

Keywords:  Autophagy; Hyperosmotic stress; Interstitial fibroblasts; Renal tubular epithelial cells; TFEB

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120238
Nat Rev Dis Primers. 2026 Oct 22. pii: 70. [Epub ahead of print]12(1):

Birt-Hogg-Dubé syndrome.

Stefan J Marciniak, Andrea Ballabio, Elizabeth P Henske, John C Kennedy, W Marston Linehan, Eamonn R Maher, Neil Rajan, Maria T Wetscherek, Kai-Feng Xu.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant tumour predisposition disorder caused by pathogenic variants in the folliculin (FLCN) gene. It is characterized by benign skin tumours, renal neoplasia and cystic lung disease, with a risk of spontaneous pneumothorax. Although historically considered rare, population genomic data indicate that FLCN pathogenic variants are substantially more common than expected from clinically ascertained cases, suggesting that many variant carriers are not currently recognized in clinical practice. Advances in the molecular biology of BHD syndrome have established that FLCN loss-of-function is associated with dysregulation of the mTORC1-TFEB lysosomal signalling pathway, which has been implicated in mouse models of BHD syndrome-associated renal and lung pathology. Clinically, diagnosis relies on recognizing characteristic patterns across dermatological, renal and pulmonary presentations, with genetic confirmation enabling cascade testing and targeted surveillance. Management is centred on lifelong renal imaging, early intervention for tumours, and prevention and treatment of pneumothorax, delivered through multidisciplinary care. Despite generally indolent renal tumour behaviour, malignant progression can occur. Ongoing research aims to improve early diagnosis through population genomics and to develop targeted therapies. These advances are likely to transform the identification and management of BHD syndrome and provide broader insights into tumour suppressor biology.

DOI: https://doi.org/10.1038/s41572-026-00745-3
Cell Mol Life Sci. 2026 Jul 22. pii: 386. [Epub ahead of print]83(1):

Metformin improves mitophagy-related pathways and mitochondrial-lysosomal homeostasis in chromosome 21 trisomic fibroblasts.

Nunzia Mollo, Rosalba Natale, Morena D'Ariano, Simona Coppola, Daniele Di Meglio, Adriana Limone, Gaetano Calì, Claudia D'Agostino, Nunzia Pastore, Daniela Sarnataro, Simona Paladino, Anna Conti, Lucio Nitsch, Antonella Izzo.

  Mitochondrial dysfunction is a core cellular abnormality in Down syndrome (DS), yet the mechanisms underlying impaired mitochondrial quality control remain poorly defined. Here, we provide an integrated characterization of the autophagy-mitophagy-lysosome axis in human trisomic fetal fibroblasts (DS-HFFs). We show that trisomic cells display a paradoxical combination of elevated basal autophagy/mitophagy-related markers and defective mitochondrial clearance, indicative of a saturated and inefficient quality control system. DS-HFFs exhibit increased steady-state levels of PINK1, PARKIN, OPTN, NDP52, LC3-II, and p62, accumulation of autophagic vacuoles, reduced autophagic flux, and impaired delivery of mitochondria to lysosomes. We further demonstrate that metformin alleviates the saturation of the autophagy-mitophagy pathway by modulating multiple components of the mitochondrial quality control pathway, including attenuation of mTOR-associated signaling, enhancement of autophagic flux and normalization of mitophagy-related protein levels. Crucially, metformin increases mitochondria-lysosome association and rescues lysosomal degradative competence as shown by increased Dq-BSA activity, and increased maturation of Cathepsin D. Together, our findings support mitophagy inefficiency due to pathway saturation as a key pathogenetic mechanism in trisomic cells and identify metformin as a pharmacological tool capable of relieving the proteostatic overload intrinsic to trisomy 21. More broadly, these results align with a model in which aneuploidy imposes a chronic proteostatic burden that compromises organelle quality control.

Keywords:  Metformin; Mitochondrial quality control; Mitophagy; PINK1-PARKIN pathway; Trisomy 21

DOI:  https://doi.org/10.1007/s00018-026-06355-2
Nat Commun. 2026 Sep 23. pii: 11057. [Epub ahead of print]17(1):

Loss of intestinal Akt elicits rapid mortality via intestinal damage which is rescued by mTORC1 activation.

Ahmed Magdy, Hyunsoo Rho, Muzamil Mushtaq, William Putzbach, Veronique Nogueira, Vaibhav Chand, Nissim Hay.

Combined Akt1 and Akt2 systemic deletion in adult mice elicits rapid mortality, preceded by body weight loss, diarrhea, and inflammation. Here, we show that lethality induced by systemic Akt1/Akt2 deletion is caused by intestinal damage, as intestinal Akt1/Akt2 deletion induces mortality phenocopying systemic deletion. Consistently, Akt ablation impairs intestinal organoid formation in vitro. Both in vivo and in vitro results show that Akt is essential for the survival of Paneth cells and survival and proliferation of Lgr5+ and transit-amplifying cells. Additional intestinal deletion of either FoxO1 or Tsc1 activates mTORC1 and rescues this phenotype. Thus, mTORC1 emerges as the most critical downstream effector of Akt in maintaining intestinal integrity. Indeed, mTORC1 inhibition by Raptor deletion phenocopies intestinal deletion of Akt1/Akt2. Remarkably, systemic Akt1/Akt2 deletion is tolerated when FoxO1 is deleted concurrently. This study unravels a critical role for Akt in maintaining intestinal homeostasis and the interplay between its downstream effectors FoxO1 and mTORC1.

DOI: https://doi.org/10.1038/s41467-026-77283-9
Am J Nephrol. 2026 Oct 23. 1

Polycystin dysfunction and cardiac electrical abnormalities in ADPKD.

Pallavi Devapatla, Chu-Yu Hsu, Hsiu Mei Hsieh-Li, Li-Yen Huang.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common inherited kidney disorders characterized by the progressive formation of renal cysts. It is a systemic disease with significant extra-renal manifestations. Among these, cardiac electrical abnormalities are increasingly recognized as clinically important yet underappreciated contributors to cardiovascular morbidity and mortality. Beyond cyst formation, pathogenic variants in PKD1 or PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively, interfere with calcium homeostasis, mechanotransduction, and mitochondrial function in both kidney and heart tissues. These molecular changes trigger a cascade of pathological events, including RAAS activation, TGF-driven fibrosis, and oxidative stress, leading to structural and electrical remodeling of the heart. These alterations contribute to cardiac electrical remodeling, manifesting clinically as QT interval and corrected QT (QT/QTc) prolongation, left ventricular hypertrophy, atrial fibrillation, ventricular arrhythmias, and other electrocardiographic abnormalities. Despite growing evidence, cardiac electrical abnormalities in ADPKD remain understudied in clinical practice. Early detection of subclinical cardiovascular abnormalities may be facilitated by electrocardiographic monitoring, cardiac imaging, and complementary biomarker assessment. Additionally, findings from iPSC-derived cardiomyocyte models support the translational potential of personalized drug-screening platforms. This review summarizes current evidence linking polycystin dysfunction to cardiac electrical abnormalities in ADPKD by integrating molecular mechanisms with experimental and clinical findings. It also highlights the need for integrated cardio-renal approaches to improve cardiovascular surveillance, risk stratification, and future therapeutic development in ADPKD.

DOI: https://doi.org/10.1159/ajn/ablag030
Cancer Lett. 2026 Oct 20. pii: S0304-3835(26)00676-2. [Epub ahead of print] 218912

AMPK signaling in cancer: Molecular insights and therapeutic opportunities.

Weiwei Jiang, Peiqiang Yan, Jingchao Wang, Xutong Xue, Daoyuan Huang, Li Chen, Yuelin Yang, Hiroyuki Inuzuka, Wenyi Wei.

  AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine kinase regarded as an indispensable energy sensor during metabolic stress, coordinating diverse biological processes, including glycolysis, the tricarboxylic acid (TCA) cycle, mitochondrial dynamics, and multiple stress-responsive signaling pathways. Growing evidence shows that dysregulated AMPK signaling plays closely linked roles in tumorigenesis. Depending on the context, AMPK signaling can suppress or promote tumor growth. Mechanistically, dysregulated AMPK kinase activity contributes to metabolic reprogramming, mitochondrial dysfunction, and epigenetic alterations, all recognized hallmarks of cancer. Consequently, targeting AMPK signaling has emerged as a promising strategy for cancer therapy. In this review, we summarize the molecular mechanisms regulating AMPK signaling, discuss its dual functions in tumor biology, highlight recent advances in AMPK-targeted therapeutic strategies, and address current challenges and future perspectives for the clinical translation of AMPK-targeted cancer therapy.

Keywords:  AMPK; AMPK activity; Cancer therapy; Energy sensor

DOI:  https://doi.org/10.1016/j.canlet.2026.218912
iScience. 2026 Nov 20. 29(11): 117826

Repressed mTORC1 signaling and transient dendritic pruning support axonal regeneration in adult zebrafish.

Anyi Zhang, Luca Masin, Steven Bergmans, Elena Putti, Shahad Albadri, Fabienne E Poulain, Filippo Del Bene, Lieve Moons.

  Dendrite degeneration is an early pathological feature following axonal damage, yet its role during successful axonal regeneration remains poorly understood. Using sparse labeling of retinal ganglion cells in adult zebrafish, we show that axonal regeneration is accompanied by a transient phase of dendritic pruning following optic nerve crush. Dendritic pruning occurs during axon elongation and is reversed after brain reinnervation. Although insulin-mechanistic target of rapamycin (mTOR) signaling is rapidly upregulated immediately after injury, it is subsequently suppressed, coinciding with dendritic pruning and sustained axonal growth. Prolonging mTOR activation through insulin treatment or direct pathway stimulation reduces dendritic pruning in an mTORC1-dependent manner but significantly delays axonal regrowth. Together, these findings identify dendritic remodeling as a temporally regulated component of axonal regeneration in zebrafish and reveal a functional trade-off between dendritic preservation and axon regrowth. This warrants further investigation on whether temporal modulation of dendritic remodeling could promote axonal regeneration in the mammalian central nervous system (CNS).

Keywords:  axonal regeneration; dendritic remodeling; insulin signaling; mTOR signaling; zebrafish

DOI:  https://doi.org/10.1016/j.isci.2026.117826
Front Immunol. 2026 ;17 1921148

TGF-β in chronic kidney disease: a controversy for decades.

Heng Wang, Jie Tian, Guoping Zheng, Yun Zhou.

  Chronic kidney disease (CKD) is characterized by persistent inflammation, maladaptive repair and progressive renal fibrosis, yet therapeutic strategies capable of effectively targeting these interconnected processes remain limited. Transforming growth factor-β1 (TGF-β1) is a central mediator of renal fibrosis but also exerts essential immunoregulatory and tissue-protective functions, creating a fundamental therapeutic paradox. Emerging evidence indicates that these divergent effects are determined not simply by TGF-β1 abundance, but by its cellular source and target, spatial and temporal context, interactions with other signaling pathways, and the transcriptional cofactors that determine downstream gene expression. This context dependence may partly explain why systemic TGF-β neutralization has shown limited clinical efficacy despite compelling preclinical evidence. In this Review, we discuss the cell-specific and stage-dependent functions of TGF-β1 in CKD, controversies surrounding the cellular origins of renal myofibroblasts, and the integration of TGF-β signaling with some signaling pathways. We further examine lessons from clinical trials and emerging therapeutic approaches designed to selectively modulate pathological TGF-β signaling, including regulation of latent TGF-β activation, receptor and Smad signaling, transcriptional cofactors, tissue-targeted delivery, and gene- and cell-based strategies. Particular attention is given to transcriptional partner selection as a mechanism of signal reprogramming. The β-catenin-TCF/FOXO1 axis provides a proof of concept whereby redirecting β-catenin from profibrotic TCF-dependent transcription toward FOXO1-associated anti-inflammatory and reparative programs may preserve beneficial TGF-β functions while limiting fibrosis. We propose that future TGF-β-targeted therapy should move beyond global pathway inhibition toward spatially, temporally and molecularly informed signal reprogramming, supported by biomarker-guided patient stratification and emerging single-cell and spatial technologies. Such precision modulation may provide a more rational strategy to suppress pathological fibrosis while preserving immune homeostasis and regenerative capacity in CKD.

Keywords:  chronic kidney disease; fibrosis; immunology; therapy; transforming growth factor-beta

DOI:  https://doi.org/10.3389/fimmu.2026.1921148
Traffic. 2026 Dec;27(4): e70056

The Lysosomal Clock: Are We Only as Old as Our Lysosomes?

Alexis Diaz Vegas, Thierry Galli.

Lysosomes are a major organelle involved in intracellular degradation, membrane traffic and metabolic signaling, but how their biochemical composition changes during normal aging remains poorly defined. Puszynska and colleagues now combine lysosome purification with metabolomics and lipidomics across tissues, species and ages to reveal a conserved signature of lysosomal aging characterized by accumulation of glycerophosphodiesters (GPDs) and cystine and remodeling of bis(monoacylglycero)phosphate (BMP). Strikingly, these changes are largely obscured in whole-tissue analyses and resemble metabolic abnormalities associated with lysosomal storage disorders, including CLN3 disease and cystinosis. The signature develops progressively with age, can predict chronological age, and is attenuated by caloric restriction in peripheral tissues but not in the brain. Within the brain, age-dependent metabolite accumulation is particularly prominent in microglia and is also detected in neurons, linking lysosomal aging to cell populations central to neurodegenerative disease. These findings define an organelle-level metabolic clock, suggesting that one might be only as young as one's lysosomes. Establishing whether GPDs, cystine and BMP remodeling merely mark lysosomal age or actively contribute to declining lysosomal degradation and membrane traffic may uncover a metabolic connection between physiological aging, lysosomal storage disorders and vulnerability to late-onset neurodegeneration.

DOI: https://doi.org/10.1111/tra.70056