bims-raghud 2026-08-09 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2026–08–09
ten papers selected by
Irene Sambri, TIGEM

Non-canonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma.
TFEB Deficiency Impairs Male Fertility Through Mitochondrial Dysfunction.
Substrate-selective mTORC1 regulation and gene dosage-dependent tissue divergence in Birt-Hogg-Dubé syndrome.
Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.
p62/SQSTM1-KEAP1 complex prevents clearance of ubiquitinated Z alpha-1 antitrypsin and aggravates liver proteotoxicity.
GOLPH3 depletion in glioblastoma cells promotes anti-tumor effects and neuronal differentiation by affecting mTOR signaling.
TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development.
Neonatal Seizures in Tuberous Sclerosis Complex: A Case Series.
Case Report: Diagnosis and treatment report and literature review of 2 cases of VHL-deficient renal cell carcinoma.
FNIP1 variants are associated with favourable metabolism in 1 million humans.

J Clin Invest. 2026 Aug 06. pii: e206334. [Epub ahead of print]

Non-canonical mTORC1-TFEB activation promotes hepatocyte plasticity and high-grade malignancy in hepatocellular carcinoma.

Chen Zhang, Xiaojuan Chao, Sha Neisha Williams, Xiaoli Wei, Anthony DiGirolamo, Alisha Bajracharya, Lichun Ma, Ming Huang, Nicholas Dunn, Wanqing Liu, Kaito Ueda, Masayuki Sugimoto, Andrea Ballabio, Hong-Min Ni, Wen-Xing Ding.

  Hepatocellular carcinoma (HCC) is heterogeneous, and hepatocyte plasticity is linked to poorer patient outcomes. A subset of human HCC harboring Tuberous Sclerosis Complex 1 (TSC1) mutations exhibits more aggressive behavior. TFEB is a master regulator of lysosomal biogenesis and cell fate. We analyzed human normal and HCC tissue arrays for TFEB and CK19 expression, as well as bulk and single-cell RNA-seq datasets from mouse and human HCC, to define TFEB-associated transcriptional programs. We performed biochemical, histological, metabolomic, and transcriptomic analyses in liver-specific Tsc1 knockout (L-Tsc1 KO) and L-Tsc1,Tfeb double KO (DKO) mice. Loss of hepatic Tsc1 led to increased phosphorylation of S6 and 4EBP1, with paradoxical increases in TFEB nuclear translocation and activation. L-Tsc1 KO mice showed increased hepatocyte plasticity, decreased HFN4α, increased YAP1 activation, and spontaneous HCC with increased SOX9 and CK19-positive biliary epithelial cell (BEC)-like cells at 8-12 months. Deletion of Tfeb dampened hepatic metabolic reprogramming and hepatocyte fate changes and inhibited tumor progression in L-Tsc1 KO mice. Increased TFEB activity was associated with increased YAP and SOX9 gene expression and high-grade malignant HCC in humans. These findings indicate that loss of hepatic TSC1 leads to non-canonical TFEB activation, promoting hepatocyte plasticity and tumor heterogeneity associated with high-grade malignancy in both mouse and human HCC. .

Keywords:  Autophagy; Cell biology; Hepatology; Liver cancer; Oncology

DOI:  https://doi.org/10.1172/JCI206334
FASEB J. 2026 Aug 15. 40(15): e72185

TFEB Deficiency Impairs Male Fertility Through Mitochondrial Dysfunction.

Hongxia Li, Guoqing Zhao, Ruojun Zong, Jia Liu, Liwei Huang, Juan Xiong, Xiaolong Pan, Lijuan Huang, Lili Wang, Danna Jia, Yiyan Zhao, Xiaoyuan Zhang, Pengkang Song, Le Zhao, Xuanqi Yu, Junyao Zhang, Huimin Lv, Xiaoyu Li, Hongyong Zhang, Ruigao Song.

  Transcription Factor EB (TFEB) is widely recognized as a key transcription factor regulating lysosomal biogenesis and autophagy. Although the TFEB gene is highly expressed in the testes, the mechanism by which it affects male fertility remains unclear. Here, we report that spermatogonia-specific deletion of TFEB in mice results in a multifaceted reproductive phenotype, including impaired fertility, compromised sperm motility, and attenuated androgen production. Immunofluorescence results showed a significant decrease in the expression levels of TNP1, a marker for spermiogenesis. Under electron microscopy, we observed abnormalities in the mitochondria of the testes and sperm. Integrated transcriptomic and biochemical analyses identified a cluster of mitochondrial-associated genes, including Star, Slc25a48, Gss, and ROMO1, with functional enrichment pinpointing disruptions in steroidogenic flux and calcium homeostasis. In summary, our study identifies TFEB as a pivotal regulator of mitochondrial integrity in the testes, the loss of which drives male subfertility through metabolic and hormonal dysregulation.

Keywords:  androgens; fertility; male; mitochondria; testis

DOI:  https://doi.org/10.1096/fj.202601937RR
Front Oncol. 2026 ;16 1848740

Substrate-selective mTORC1 regulation and gene dosage-dependent tissue divergence in Birt-Hogg-Dubé syndrome.

Zhi-Lie Cao, Si-Cheng Zhao, Feng Lin, You-Huang Liu, Xu-Tao Hong, Ling-Ye Hong, Li-Qi Xu, Fei-Ping Li, Hong-Yuan Yu, Wu-Gen Yao, Wei-Ying Chen.

  Birt-Hogg-Dubé (BHD) syndrome, caused by mutations in the tumor suppressor gene FLCN, has traditionally been classified as a classic "mTORopathy" characterized by global mTORC1 activation. Recent structural and multi-omic studies have fundamentally challenged this view, revealing that FLCN functions as a GAP for RagC/D to govern substrate-selective mTORC1 regulation. Synthesizing emerging evidence, we describe an integrated pathogenic framework: biallelic FLCN inactivation drives renal tumorigenesis via constitutive MiT/TFE nuclear accumulation and metabolic reprogramming, whereas haploinsufficiency suffices to disrupt structural integrity in the lung and skin. By reconciling the "mTORC1 paradox" through the lens of gene dosage and temporal signaling dynamics, we highlight novel therapeutic vulnerabilities targeting MiT/TFE factors and kinase rewiring, providing a rationale for organ-specific precision medicine in BHD.

Keywords:  Birt-Hogg-Dubé syndrome; FLCN; TFEB; haploinsufficiency; mTORC1; renal cell carcinoma; substrate selectivity

DOI:  https://doi.org/10.3389/fonc.2026.1848740
Nat Commun. 2026 Aug 07. pii: 8011. [Epub ahead of print]17(1):

Vitamin B12 alleviates spliceosomopathy via phospholipid remodeling.

Jonathan Kölschbach, Hormos S Dafsari, Emily Baum, Anna Löhrke, Chun Kew, Ivan Dikic, Wenming Huang, Adam Antebi.

mRNA splicing represents a fundamental level of gene regulation that alters proteomic diversity and cellular state. Its dysfunction can profoundly rewire metabolism, yet underlying mechanisms remain elusive. Here, we investigate Verheij syndrome, caused by mutations in core splicing factor PUF60, using a Caenorhabditis elegans model, human cell lines, and patient-derived samples. We demonstrate that RNP-6/PUF60 deficiency disrupts splicing of genes governing one-carbon metabolism and phospholipid remodeling, impairing S-adenosylmethionine/S-adenosylhomocysteine cycling and phosphatidylcholine synthesis. These perturbations trigger the integrated stress response and compromise mTORC1 signaling, causing developmental growth defects. Vitamin B12 supplementation restores metabolic balance by reactivating S-adenosylmethionine-dependent phospholipid remodeling and mTORC1 activity, effectively rescuing Verheij-like phenotypes. Similar responses arise from perturbing another splicing factor, PRP-19. Mechanistically, intron retention of nhr-114/HNF4 transcription factor drives these phenotypes, while restoring its splicing rescues them. Our findings implicate vitamin B12-dependent one-carbon metabolism as a metabolic modulator with therapeutic potential to mitigate Verheij syndrome and other spliceosomopathies.

DOI: https://doi.org/10.1038/s41467-026-76295-9
J Biol Chem. 2026 Aug 07. pii: S0021-9258(26)02282-9. [Epub ahead of print] 113410

p62/SQSTM1-KEAP1 complex prevents clearance of ubiquitinated Z alpha-1 antitrypsin and aggravates liver proteotoxicity.

Nunzia Pastore, Sergio Attanasio, Francesco Annunziata, Claudia D'Agostino, Veronica Maffia, Rita Colonna, Teresa Giuliano, Rosa Ferriero, Iolanda Boffa, Donna Palmer, Philip Ng, Rossella De Cegli, Massimo D'Agostino, Florian Rosenberger, Pavel Strnad, Joseph E Chambers, Stefan J Marciniak, Jeffrey Teckman, Pasquale Piccolo, Nicola Brunetti-Pierri.

Liver disease in Alpha-1 antitrypsin deficiency (AATD) is caused by the toxic accumulation of mutant Z alpha-1 antitrypsin (Z-AAT) within the endoplasmic reticulum (ER) of hepatocytes. Livers from PiZ transgenic mice expressing the human Z-AAT and AATD patients were both found to have increased p62/SQSTM1, a multifunctional protein involved in protein homeostasis, consistent with previous reports. However, whether p62/SQSTM1 is a marker of Z-AAT globules or plays an active role in Z-AAT proteostasis is unclear. The goal of this study was to elucidate the involvement of p62/SQSTM1 in the formation of Z-AAT globules that are responsible for liver injury in AATD. In the present study, we found that p62/SQSTM1 decorated ubiquitin-positive, Periodic-Acid Shiff-diastase-resistant Z-AAT globules and interacted with Z-AAT at the ER-cytosol interface. Genetic ablation of p62/SQSTM1 in PiZ mice (PiZ;p62-/-) led to marked reduction in hepatic Z-AAT globules and polymers, and decreased serum Z-AAT, highlighting a central role for p62/SQSTM1 in disease pathogenesis. Moreover, hepatocyte-specific somatic deletion of the ubiquitin-association (UBA) domain of p62/SQSTM1 reduced Z-AAT aggregation. Furthermore, KEAP1 was identified as a binding partner of p62/SQSTM1-Z-AAT complex, leading to nuclear translocation and activation of NRF2. Inhibition of KEAP1-p62/SQSTM1 interaction reduced the abundance of p62 and phosphorylated p62, decreased intracellular Z-AAT, and redistributed NRF2 to the cytoplasm. In conclusion, this study identifies p62/SQSTM1 as a regulator of Z-AAT proteostasis and link Z-AAT/p62 accumulation to KEAP1 sequestration and NRF2 pathway activation in liver disease due to Z-AAT.

DOI: https://doi.org/10.1016/j.jbc.2026.113410
Eur J Cell Biol. 2026 Jul 29. pii: S0171-9335(26)00027-0. [Epub ahead of print]105(3): 151556

GOLPH3 depletion in glioblastoma cells promotes anti-tumor effects and neuronal differentiation by affecting mTOR signaling.

Anna Frappaolo, Gianluca Zaccagnini, Riccardo Rizzo, Luisa Salvatori, Maria Grazia Giansanti.

  Glioblastoma is the most aggressive primary brain tumor in adults. Resistance of glioblastoma to the standard chemotherapy agent temozolomide (TMZ) correlates with the expression of the DNA repair enzyme O6-Methylguanine-DNA methyltransferase (MGMT). Additionally, tumor initiation and recurrence are associated with a subpopulation of glioblastoma stem cells (GSCs) which exhibit self-renewal properties, multipotency, and resistance to both chemotherapy and radiotherapy. To identify novel molecular biomarkers and therapeutic targets, we investigated the possible role of the oncoprotein Golgi phosphoprotein 3 (GOLPH3) in glioblastoma. GOLPH3 is overexpressed in many solid tumors and confers resistance to DNA-damaging chemotherapeutic agents. Its overexpression is also associated with poor prognosis in a variety of cancers, including glioblastoma. Here, we show that GOLPH3 knockdown in U87MG glioblastoma cells inhibits cell proliferation, promotes senescence and induces striking cellular and molecular changes toward a neuron-like phenotype. We analyzed the constitutive expression of GOLPH3, MGMT and mechanistic target of rapamycin (mTOR) signaling proteins in U87MG cells and in three GSCs representative of the three glioblastoma molecular subtypes. Our results suggest that these glioblastoma cell models may exhibit distinct responses to mTOR inhibition and TMZ. Finally, we show that GOLPH3 depletion reduces the activity of both mTOR complex 1 and 2 leading to decreased phosphorylation of their respective downstream targets S6K and Akt in both U87MG cells and the BT379 GSCs subtype. Our findings identify a potential therapeutic vulnerability that can be exploited to develop patient-tailored treatments in glioblastoma.

Keywords:  GOLPH3; Glioblastoma stem cells; U87MG glioblastoma cells; mTOR signaling

DOI:  https://doi.org/10.1016/j.ejcb.2026.151556
PLoS Biol. 2026 Aug;24(8): e3003902

TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development.

Canan Doganli, Oskar Kaaber Thomsen, Daniel A Baird, Yeasmeen Ali, Menachem V K Sarusie, Enrique Audain, Line Jeanett Jessen, Pauline Munck Truelsen, Johanne Bay Mogensen, Maria Schrøder Holm, Kateřina Apolínová, Lorenzo Buttò, Maria Diamanti, Jindřiška Leischner Fialová, Emma M Wade, Stephen P Robertson, Lotte Bang Pedersen, Laurent Argiro, Fabienne Lescroart, Marc-Phillip Hitz, Søren Tvorup Christensen, Lars Allan Larsen.

Pathogenic variants in the genes encoding the non-canonical TGFB signaling components TAK1 (MAP3K7), TAB2 and PKA-Cα (PRKACA) cause rare multisystem disorders, which may include congenital heart disease (CHD). To investigate the role of TAK1 signaling in CHD, we performed genetic analysis of CHD patients and discovered an increased burden of rare TAB2 and TAK1 variants in patients with extracardiac abnormalities. To address the mechanism of TAK1 in heart development, we performed experiments in cell and animal models. Zebrafish tak1 and tab2 mutants presented with cardiac and extracardiac developmental defects, and tak1 mutant hearts showed downregulation of genes encoding core cardiac transcription factors, sarcomeric proteins and extracellular matrix proteins. In vitro experiments indicated that TAK1 via TAB2 and PKA-Cα is activated at the primary cilium during cardiomyogenesis; activation at this site is enhanced by TGFB/BMP ligands. Inactivation of TAK1 inhibited ciliary signaling and cardiomyocyte differentiation, and patient-derived TAK1 variants reduced its ciliary localization. In conclusion, our data establish a pivotal role for TAK1 and its upstream regulators at the primary cilium in heart development and syndromic CHD.

DOI: https://doi.org/10.1371/journal.pbio.3003902
Ann Child Neurol Soc. 2026 Jun;4(2): 145-149

Neonatal Seizures in Tuberous Sclerosis Complex: A Case Series.

Kristina Jülich, Kristen Arredondo.

   Background: Epilepsy affects up to 90% of patients with tuberous sclerosis complex (TSC); earlier seizure onset is associated with worse neurocognitive outcomes. The incidence of neonatal seizures in TSC is unknown, although in a recent multicenter trial 23% of infants with TSC were excluded prior to randomization because of pre-existing seizures prior to age 4 months, suggesting that neonatal or early infantile seizures may be a common occurrence.
Aims: We aimed to determine the rate of neonatal seizures in our cohort of TSC patients.
Methods: We performed a single-center medical records review of patients with TSC who were seen between 2020 and 2025 to identify patients with neonatal seizure onset.
Summary and Conclusions: Of six patients with data from the neonatal period, four (67%) had neonatal seizures. Two had confirmed electrographic seizures in the first week of life, and another two had clinical seizure onset during the neonatal period. All patients with neonatal seizures had TSC2 and developed drug-resistant epilepsy, and two of four developed infantile spasms despite intensive early medical management, including vigabatrin. The two patients without neonatal seizures had TSC1 and mosaic TSC2, respectively. They have not developed epilepsy and have had milder neurodevelopmental impairment.In conclusion, data from our center suggest that neonatal seizures may be common in TSC, especially in high-risk infants with TSC2 with highly epileptogenic lesions. With recent preliminary data about safety and efficacy of mTOR inhibitor treatment in infants with TSC, early EEG monitoring should be considered.

Keywords:  TSC1; TSC2; cortical dysplasia; early onset epilepsy; electroencephalogram; electrographic

DOI:  https://doi.org/10.1002/cns3.70061
Front Oncol. 2026 ;16 1645910

Case Report: Diagnosis and treatment report and literature review of 2 cases of VHL-deficient renal cell carcinoma.

Yanchen Wang, Tongbin Gao, Na Ren, Yuxuan Liu, Qingxuan Li, Xiaoyan Guo.

  Von Hippel-Lindau (VHL) disease is a rare familial autosomal dominant disorder with an incidence rate of approximately 1 in 36,000. It primarily results from mutations or inactivation of the VHL tumor suppressor gene located on chromosome 3p25-p26. The hallmark of this disease is hereditary hemangioblastoma, which can affect multiple organs and systems, including the brain (commonly infratentorial), spinal cord, retina, and internal organs such as the kidneys, adrenal glands, and pancreas. Less commonly, lesions may include papillary cystadenomas and endolymphatic sac tumors (ELST), which can form in the epididymis or broad ligament. The leading causes of death in these patients are hemangioblastomas and renal cell carcinoma of the central nervous system. Due to the multidisciplinary nature of the disease, diagnosis and management require a multidisciplinary team (MDT) consultation and collaboration among various specialties. Clinical diagnosis, genetic implications, and prognosis must be assessed comprehensively, with genetic testing confirming the diagnosis. Cases of VHL are exceptionally rare in clinical practice, and there remains a significant unmet need for effective treatments, particularly in rare tumors. Misdiagnosis and mistreatment are common, and repeated surgical interventions can exacerbate kidney damage. Early and accurate diagnosis, followed by proactive treatment, can significantly improve prognosis. Recently, our department admitted two patients with VHL-deficient renal cell carcinoma. Through surgery, radiofrequency ablation, and subsequent targeted therapy, the therapeutic outcomes were highly favorable. This report introduces the treatment of these two cases and provides a literature review on the current progress in the diagnosis, treatment, and prognosis of VHL-deficient renal cell carcinoma. Additionally, it discusses data on the screening of VHL patients and their close relatives, while emphasizing the optimization of individualized management for renal cell carcinoma to enhance the understanding, diagnosis, and treatment of the disease.

Keywords:  VHL disease; VHL-deficient renal cell carcinoma; hypoxia-inducible factor; screening test; targeted immunotherapy drugs

DOI:  https://doi.org/10.3389/fonc.2026.1645910
Nature. 2026 Aug 05.

FNIP1 variants are associated with favourable metabolism in 1 million humans.

Regeneron Genetics Center

Altered energy metabolism is a shared driver across cardiometabolic diseases-the leading cause of death globally1. Energy metabolism varies between individuals and is partly heritable2-9. Here, to investigate the genetic basis of energy metabolism, we perform an exome-sequencing analysis of 1,032,116 people from America, Europe and Asia, and estimate associations between rare protein-coding variants and the ratio of triglyceride to high-density-lipoprotein cholesterol (TG:HDL)-an energy-state biomarker that we associate with diverse cardiometabolic risk factors and diseases. We identify 59 independent genes (P < 1.04 × 10-7) that are enriched for liver- and adipose-expressed master regulators of energy balance, storage and metabolism; 23 (39%) of these genes encode approved or clinical-stage drug targets. Ultra-rare protein-truncating variants in FNIP1 (allele frequency, 0.01%), which encodes a suppressor of energy expenditure and mitochondrial metabolism, are associated with a lower TG:HDL ratio, lower liver fat, lower glycaemia, favourable fat distribution and around 60% lower odds of cardiometabolic disease. FNIP1 knockdown in primary human hepatocytes induces lipid breakdown and lysosomal gene expression, while combined hepatic knockdown of Fnip1 with its paralogue Fnip2 or knockdown of its interactor Flcn protect against weight gain, reduce liver fat and enhance insulin sensitivity in mice fed a high-fat diet. Our study implicates the FNIP1 pathway in human energy metabolism and highlights its inhibition as a potential therapeutic strategy in cardiometabolic disease.

DOI: https://doi.org/10.1038/s41586-026-10864-2