bims-raghud 2025-11-16 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2025–11–16
nine papers selected by
Irene Sambri, TIGEM

Tuberous sclerosis complex-associated renal cell carcinoma, an underappreciated form of familial renal cancer, is characterized by activation of the TFEB/TFE3 pathway.
Transcription Factor EB (TFEB) Expression and Localization in the Third-Trimester Placenta.
Dual activation of autophagy and mTOR by TFE3 fusions promotes tumorigenesis in rearranged renal cell carcinoma.
Uncomplexed-TSC1 deploys novel mTORC1-independent pathway to exacerbate the liver glycogen storage in TSC.
Kidneys in Children with Tuberous Sclerosis Complex-An Up-to-Date Review.
A Case of TSC2/PKD1 Contiguous Gene Deletion Syndrome With Proven Kidney Pathology.
SGLT2 Inhibitors in ADPKD: Mechanistic Insights and Therapeutic Promise.
mTORC1 regulates autophagosomal components recycling through SNX16 phosphorylation.
Whole Exome Sequencing in Children With Autoimmune Hepatitis Identified Mutations in Genes Involved in the mTORC1 Signaling Pathway.

Hum Mol Genet. 2025 Nov 11. pii: ddaf173. [Epub ahead of print]

Tuberous sclerosis complex-associated renal cell carcinoma, an underappreciated form of familial renal cancer, is characterized by activation of the TFEB/TFE3 pathway.

Christopher J Ricketts, Cathy D Vocke, Martin Lang, Julia Medina Velazquez, Vaishnavi S Srirama, Daniel R Crooks, Dionna Gamble, Chiara Di Malta, Krista L Reynolds, Rabindra Gautam, Mark Raffeld, Maria J Merino, Andrea Ballabio, Mark W Ball, W Marston Linehan.

   OBJECTIVE: To describe the genetic, phenotypic, and pathologic manifestations of patients presenting with inherited kidney cancer and germline variants of the Tuberous Sclerosis Complex (TSC) genes.
MATERIALS AND METHODS: Inherited kidney cancer patients were screened for germline RCC susceptibility gene variants and patient histories and clinical evaluations were performed. Renal tumors were evaluated for somatic genetic alterations by DNA sequencing and mRNA expression analysis by RNAseq and immunohistochemical analyses were performed.
RESULTS: Nine distinct germline TSC1/TSC2 variants were identified in 13 patients, including seven known or likely pathogenic alterations. Five patients presented with a clinical diagnosis of TSC, and eleven patients had a genetic diagnosis of TSC. Nine patients had bilateral RCC and nine had multifocal RCC. The average initial age at diagnosis of RCC was 47 years old. The TSC-associated tumors demonstrated a variety of histologies including ccRCC, RCC with clear cell and papillary features, chromophobe RCC, and oncocytoma; with ccRCC being the most prevalent. Loss of heterozygosity or secondary somatic alteration of TSC1/TSC2 was observed in ~ 37% of tumors. RNAseq analysis demonstrated specific expression patterns associated within histologically defined tumor clusters and increased expression of CLEAR genes activated by the TFE3/TFEB transcription factors, including GPNMB and NPC1 which were confirmed with immunohistochemistry.
CONCLUSION: This study confirms the importance of screening individuals with a family history of kidney cancer for TSC1/TSC2 germline variants, even in the absence of canonical TSC manifestations, and indicates a critical role of TFE3 and TFEB as drivers of human TSC-deficient renal cell carcinoma.

Keywords:  GPNMB; Loss of heterogeneity; Renal cell carcinoma; TFE3/TFEB; TSC1/TSC2; Tuberous Sclerosis Complex (TSC)

DOI:  https://doi.org/10.1093/hmg/ddaf173
Int J Mol Sci. 2025 Oct 22. pii: 10294. [Epub ahead of print]26(21):

Transcription Factor EB (TFEB) Expression and Localization in the Third-Trimester Placenta.

Cinzia Giacometti, Alessandro Ambrosi, Serena Cavaliere, Anna Caliò, Daniele Mautone, Guido Martignoni.

  Transcription factor EB (TFEB) is expressed at high levels in the trophoblast cells of the placenta, where it plays a critical role in regulating normal vascularization. Preeclampsia (PE) is a severe complication of pregnancy with a high incidence of maternal and fetal morbidity and mortality. Gestational diabetes (GD) is a metabolic disease that can affect placental villous maturation and villous vascularity. We analyzed the expression of three different antibodies: TFEB from Invitrogen (TFEB-INV), which detects endogenous levels of TFEB only when phosphorylated at Ser211; TFEB from Bethyl Labs (TFEB-B), which recognizes and binds E-box sequences; and TFEB from Santa Cruz (C-6) (TFEB-SC), which is specifically used for epitope mapping between 440 and 470. We evaluated the presence/absence of TFEB in six placental districts: syncytiotrophoblast (STB), cytotrophoblast (CTB), extravillous trophoblast (EVT), syncytial knots, stem villi vessels, and villous capillaries. TFEB-B was significantly expressed in the stem villi vessels, STB, and villi vessels of GD cases. The lack of TFEB expression in late-onset PE appears to corroborate the role of TFEB in vascular remodeling during placental development. The positive results in STB and vessels in GD cases, regardless of the histological diagnosis, may suggest that the expression of TFEB mitigates hypoxic injury via the Akt/mTOR pathway.

Keywords:  TFEB; gestational diabetes; immunohistochemistry; preeclampsia

DOI:  https://doi.org/10.3390/ijms262110294
Carcinogenesis. 2025 Nov 11. pii: bgaf080. [Epub ahead of print]

Dual activation of autophagy and mTOR by TFE3 fusions promotes tumorigenesis in rearranged renal cell carcinoma.

Ruina Wu, Xiaotong Wang, Miaomiao Tian, Xue Wei, Xuan Wang, Shengbing Ye, Rusong Zhang, Qiuyuan Xia, Ru Fang, Qiu Rao.

  TFE3-rearranged renal cell carcinoma (TFE3-RCC), an aggressive kidney cancer predominantly affecting pediatric and young adult populations, is driven by Xp11.2 rearrangeds generating oncogenic TFE3 fusion proteins. Although these fusions define the disease, their mechanistic roles remain elusive. Here, lentiviral-mediated overexpression of PRCC-TFE3 or NONO-TFE3 in RCC models triggered nuclear rearranged of fusion proteins and significantly accelerated tumor proliferation both in vitro and in vivo. Our integrated RNA sequencing (RNA-seq) and Chromatin Immunoprecipitation sequencing (ChIP-seq) analyses mechanistically revealed that TFE3 fusions directly bind to promoters of lysosome and mTOR signaling pathway genes, leading to transcriptional activation of this pathway. Moreover, the fusions aberrantly escaped canonical mTOR signaling pathway regulation and paradoxically hyperactivated phospho-mTOR signaling. Importantly, dual inhibition of the autophagy and mTOR pathways synergistically suppressed tumor growth, exceeding the efficacy of single-agent treatments. These data demonstrate that co-targeting these TFE3-regulated pathways represents a promising therapeutic strategy for this intractable malignancy.

Keywords:  TFE3 fusion protein; TFE3-rearranged renal cell carcinoma; autophagy; mTOR signaling pathway

DOI:  https://doi.org/10.1093/carcin/bgaf080
Cell Death Dis. 2025 Nov 14. 16(1): 829

Uncomplexed-TSC1 deploys novel mTORC1-independent pathway to exacerbate the liver glycogen storage in TSC.

Xiaoqiao Yue, Yanping Zhang, Na Zhao, Tao Lang, Guangxin Chen, Qiuhong Xiong, Lei Gao, Wenjing Wang, Ping Li, Changxin Wu.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by inactivating mutations in TSC1 or TSC2 gene, leading to mTORC1 hyperactivation. However, mTORC1-independent mechanisms in this disorder remain poorly understood. In the study, excess glycogen storage was found in Tsc1-/- cells, Tsc1+/- and Tsc1c.2500-2503delAACA mice, as well as in Tsc2-/- cells, Tsc2+/- and Tsc2c.1113delA mice, with more pronounced accumulation in models with TSC2 defects. Mechanistically, the deficiency of TSC1 or TSC2 gene caused redundant uncomplexed-TSC2 or TSC1 protein, respectively. Strikingly, only uncomplexed-TSC1 downregulated the histone demethylase KDM5A, which in turn increased H3K4me3 levels at the METTL3 promoter to enhance its expression. The upregulated m6A "writer" protein METTL3 cooperated with the "reader" protein IGF2BP2 to stabilize GYS2 mRNA, causing the upregulation of GYS2 resulting in the glycogen storage. Thus, our study uncovered a novel mTORC1 independent pathway (TSC1-KDM5A-METTL3-IGF2BP2-GYS2) that underlies the excess glycogen storage, and that synergy of mTORC1-dependent and independent pathways leads to the more pronounced glycogen storage with TSC2 defects compared to those with TSC1 defects, reflecting the more severer clinical phenotypes in TSC patients with TSC2 mutations. Importantly, the restoration of glycogen homeostasis and significant amelioration of liver lesion in TSC2 defect models after the combination treatment of pharmacological inhibitors targeting mTORC1 and METTL3, unveil a potential clinic intervention for TSC patients to whom mTORC1 inhibitors are less effective or even ineffective.

DOI: https://doi.org/10.1038/s41419-025-08161-3
J Clin Med. 2025 Nov 03. pii: 7805. [Epub ahead of print]14(21):

Kidneys in Children with Tuberous Sclerosis Complex-An Up-to-Date Review.

Anna Maria Wabik, Jakub Pytlos, Aneta Michalczewska, Piotr Skrzypczyk.

  Background: Tuberous sclerosis complex (TSC) is a rare genetic disorder characterized by the growth of benign tumors in various organ systems, with particularly significant effects on the kidneys. Renal manifestations of TSC include angiomyolipomas (AMLs), renal cysts, and a higher risk of renal cell carcinoma (RCC). Nephrological monitoring is crucial for the early detection of kidney changes, the management of hypertension, and the assessment of the risk of developing chronic kidney disease. Ultrasound is typically the initial imaging choice for diagnosis and monitoring, with magnetic resonance imaging (MRI) being a preferred imaging modality for long-term surveillance. Patients with TSC have an increased risk of arterial hypertension, renal artery stenosis, and urolithiasis. In some patients, the co-occurrence of TSC and autosomal dominant polycystic kidney disease (ADPKD) is caused by the TSC2/PKD1 contiguous gene syndrome (CGS). The primary medical treatment for TSC is a mammalian target of rapamycin kinase inhibitors (mTOR), as they effectively shrink tumors, often reducing or eliminating the need for surgical intervention. Methods: This article aims to review the most recent literature on the diagnosis and management of renal lesions in tuberous sclerosis complex (TSC), with a particular focus on the role of various imaging techniques. Conclusions: Given the multifactorial nature of this disease, this review emphasizes the importance of a multidisciplinary approach, including various imaging methods, to improve the care and treatment outcomes of children with tuberous sclerosis complex.

Keywords:  angiomiolipoma; chronic kidney disease; diagnostic imaging; magnetic resonance imaging; renovascular hypertension; tuberous sclerosis complex; ultrasound

DOI:  https://doi.org/10.3390/jcm14217805
Kidney Med. 2025 Nov;7(11): 101108

A Case of TSC2/PKD1 Contiguous Gene Deletion Syndrome With Proven Kidney Pathology.

Rei Kamitani, Kohkichi Morimoto, Shinya Morita, Eri Arai, Toshiki Takenouchi, Yoshifumi Ubara, Mototsugu Oya.

  TSC2/PKD1 contiguous gene deletion syndrome (PKDTS) is characterized by poor renal prognosis. We encountered a female patient with a history of facial angiofibromas since childhood who developed seizures and was subsequently diagnosed with tuberous sclerosis complex. The patient later progressed to kidney failure requiring replacement therapy at 23 years of age. Imaging studies showed polycystic kidney disease (PKD) and angiomyolipoma (AML), followed by renal hemorrhage in both kidneys. Genetic testing showed a heterozygous deletion involving the TSC2 and PKD1 genes on chromosome 16, confirming the diagnosis of PKDTS. To elucidate the cause of her kidney dysfunction, a pathohistological analysis of renal tissue showed that most of the renal parenchyma was replaced by cystic formations and scattered AML masses. The cysts were derived from both the proximal and distal tubules, a feature consistent with PKD. Renal hemorrhage was presumed to result from vascular disruption and rupture of the internal elastic lamina because of cyst and AML progression. The combination of extensive renal cyst formation related to PKD1 deletion and AML lesions corresponding to TSC2 deletion may contribute to the rapid progression of kidney dysfunction in patients with PKDTS.

Keywords:  Angiomyolipoma; polycystic kidney disease; renal hemorrhage; tsc2/pkd1 contiguous gene deletion syndrome; tuberous sclerosis complex

DOI:  https://doi.org/10.1016/j.xkme.2025.101108
J Am Soc Nephrol. 2025 Nov 10.

SGLT2 Inhibitors in ADPKD: Mechanistic Insights and Therapeutic Promise.

Marie Therese Bou Antoun, Abdul Hamid Borghol, Levon Souvalian, Mohamad Hadla, Georges Abboud, Ahmad Ghanem, Fadi George Munairdjy Debeh, Jean Marc Mardirossian, Mahdi Salih, Pranav S Garimella, Volker Vallon, Fouad T Chebib.

ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and a leading cause of kidney failure worldwide. Disease progression is driven by cyst expansion, tubular injury, and maladaptive metabolic and hemodynamic changes. Tolvaptan remains the only FDA-approved disease-modifying therapy, yet its tolerability and safety profile highlight the need for additional strategies. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), initially developed for glycemic control, have demonstrated robust kidney- and cardio- protective effects across diverse patient populations, including those without diabetes. By lowering intraglomerular pressure, metabolic reprogramming, and attenuating hypoxic microenvironment and inflammation, SGLT2i target mechanisms that are relevant to ADPKD. However, concerns that SGLT2i may provoke osmotic diuresis and activate vasopressin led to systematic exclusion of patients with ADPKD from pivotal outcome trials. The 2025 KDIGO ADPKD guidelines explicitly advise against the use of SGLT2i for slowing kidney function decline in ADPKD. In this review, we examine mechanistic intersections between SGLT2i and ADPKD pathophysiology, summarize available preclinical and early clinical data, and discuss ongoing large trials designed to address safety and efficacy of SGLT2i in patients with ADPKD. We also highlight the importance of genetic heterogeneity, as most ongoing trials are enriched for rapid progressors carrying PKD1 or PKD2 pathogenic variants, while other genotypes such as DNAJB11, ALG8, and ALG9, often associated with greater interstitial fibrosis, are underrepresented. Substratification of patients by genotype, risk of progression, and comorbidities will be essential to guide precision application of SGLT2i. Whether SGLT2i can ultimately be positioned as an adjunctive or standalone therapy for ADPKD remains unresolved.

DOI: https://doi.org/10.1681/ASN.0000000943
Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2511069122

mTORC1 regulates autophagosomal components recycling through SNX16 phosphorylation.

Huilin Que, Fengping Liu, Yang Chen, Wenmin Tian, Shuaixin Gao, Catherine C L Wong, Yan Li, Shixuan Wang, Xianbin Meng, Yueguang Rong.

  During autophagy, the contents enclosed within autophagosomes are degraded, while the outer membrane components are recycled from autolysosomes by the recycler complex through the recently discovered autophagosomal components recycling (ACR) process. This recycling is essential for maintaining autophagic activity. However, the molecular machinery and upstream regulatory mechanisms driving this recycling process remain poorly understood. Here, we identify SNX16 as a key component of the recycler complex, which localizes to autolysosomes and is required for ACR. SNX16 functions in ACR by regulating recycler complex formation, facilitating cargo recognition, and mediating the connection between STX17-SNX4-SNX5 and dynein-dynactin complexes. In addition, SNX16-cargo interactions are regulated by two ACR-related small GTPases, Rab32 and Rab38. Importantly, mTORC1 phosphorylates SNX16 to regulate ACR by inhibiting its interactions with STX17 and other recycler components, thus preventing recycler complex formation. Taken together, our findings identify SNX16 as a recycler component and establish a link between mTORC1 and ACR.

Keywords:  SNX16; autophagosomal components recycling; autophagy

DOI:  https://doi.org/10.1073/pnas.2511069122
Gastro Hep Adv. 2026 ;5(1): 100808

Whole Exome Sequencing in Children With Autoimmune Hepatitis Identified Mutations in Genes Involved in the mTORC1 Signaling Pathway.

Léa-Philippine Gaigne, Caroline Besnard, Orianne Debeaupuis, Artem Degtiar, Duong Ho Nhat, Marie-Claude Stolzenberg, Fatou Camara, Olivier Pellé, Adrien Schvartz, Mélodie Perin, Marion Almes, Amaria Darmellah-Remil, Emmanuel Gonzales, Antoine Gardin, Dalila Habes, Sylvie Destombe, Eleonora De Martin, Jean-Charles Duclos-Vallée, Peter D Arkwright, Frédéric Rieux-Laucat, Emmanuel Jacquemin, Aude Magerus.

   Background and Aims: Autoimmune hepatitis (AIH), a severe immune-mediated liver disease resulting from defective immune tolerance, was thought to be caused by monogenic predisposition with possible external triggers. The development of AIH in monogenic primary immune deficiencies prompted us to search for causative genetic defects in AIH.
Methods: Twenty-two children with AIH were included for whole exome sequencing analysis. Data were analyzed with an in-house software, combined with in silico tools and confirmed by Sanger sequencing. Mechanistic target of rapamycin (mTOR) pathway activation was assessed by phosphoS6-RP expression by fluorescence activated cells sorting.
Results: In six children with type 1 or type 2 AIH, seven rare missense candidate variants with damaging predictive scores were identified in five genes involved in the regulation of the mTOR complex 1 (mTORC1) signaling pathway (RRAGC, LAMTOR3, MTOR, TSC2, and PRKAG1). Excess of phosphorylated-S6 ribosomal protein expression both ex vivo by monocytes and in vitro by activated T cells demonstrated an abnormal activation of mTORC1 in five out of six tested patients. Persistent mTORC1 activation in starved activated T cells could be abolished by mTOR inhibitor.
Conclusion: These data showed that pediatric patients with AIH-1 or AIH-2, especially when burdened with poly-autoimmunity, may carry mutations in key partners of the mTORC1 signaling pathway. Moreover, even without identified genetic defect, we observed a deregulation of the mTOR pathway in five out of six tested patients. These results shed new light on the pathogenesis of AIH. Moreover, they suggested that the patients could benefit from specific targeted agents such as mTOR inhibitors.

Keywords:  Autoimmune Hepatitis; Genetics Pediatric Auto-Immunity Rapamycin; mTOR Pathway

DOI:  https://doi.org/10.1016/j.gastha.2025.100808