bims-raghud 2025-06-29 papers

Issue of 2025–06–29
five papers selected by
Irene Sambri, TIGEM

Free Radic Biol Med. 2025 Jun 24. pii: S0891-5849(25)00787-7. [Epub ahead of print]

Sestrin2 improves intestinal ischemia-reperfusion injury through the TFEB-mediated autophagy/lysosomal pathway.

Jing-Yuan Xie, Man Ye, Jie Luo, Ning Hu, Yi-Guo Zhang, Le-le Zhang, Zi-Yi Wen, Xiang-Yun Fu, Rong Chen, Qing-Tao Meng.

Sestrin2 is a stress-inducible protein that exhibits protective effects against ischemia-reperfusion injury in various organs. However, the specific roles and mechanisms of Sestrin2 in intestinal ischemia-reperfusion (IIR) injury have yet to be fully elucidated. The present study aims to investigate the role of Sestrin2 in intestinal IIR injury and its underlying mechanisms. We found that in the IIR model of C57BL/6J mice, Sestrin2 expression increased following IIR injury, accompanied by enhanced lysosomal activity and autophagy activation. Further cellular experiments demonstrated that overexpression of Sestrin2 increased autophagic flux, enhanced lysosomal activity, and mitigated cellular injury. These effects were abrogated by Sestrin2 knockdown. Additionally, we discovered that Sestrin2 interacts with transcription factor EB (TFEB), and that knockdown of Sestrin2 resulted in decreased nuclear translocation of TFEB, leading to a reduction in autophagic flux due to impaired lysosomal function. The TFEB activator (TFEB A1) promoted TFEB nuclear translocation and reversed autophagy/lysosomal pathway (ALP) dysfunction and cellular damage caused by Sestrin2 knockdown. In conclusion, Sestrin2 protects against IIR injury by promoting TFEB nuclear translocation, enhancing lysosomal activity, accelerating autophagosome turnover and substrate degradation, and increasing autophagic flux. These findings provide novel insights and potential targets for the treatment of IIR injury.

Keywords: Intestinal ischemia-reperfusion; Lysosomal activation; Sestrin2; TFEB; autophagy

DOI: https://doi.org/10.1016/j.freeradbiomed.2025.06.037

J Biol Chem. 2025 Jun 19. pii: S0021-9258(25)02250-1. [Epub ahead of print] 110400

Rag GTPases control lysosomal acidification by regulating v-ATPase assembly in Drosophila.

Ying Zhou, Xiaodie Yang, Wenyu Xu, Sulin Shen, Weikang Fan, Guoqiang Meng, Yang Cheng, Yingying Lu, Youheng Wei.

The Rag GTPases play an important role in sensing amino acids and activating the target of rapamycin complex 1 (TORC1), a master regulator of cell metabolism. Previously, we have shown that GDP-bound RagA stimulates lysosome acidification and autophagic degradation, which are essential for young egg chamber survival under starvation in Drosophila. However, the underlying mechanism is unclear. Here we demonstrate that the GDP-bound RagA breaks the physical interaction between chaperonin containing tailless complex polypeptide 1 (CCT) and Vacuolar H+-ATPase (v-ATPase) subunit V1, and thus promotes the assembly of active v-ATPase and increases the lysosomal acidification. Consistently, knockdown of CCT complex components rescued the accumulation of defective autolysosomes in RagA RNAi. Moreover, the knockdown of Lamtor4, a component of lysosomal adaptor and MAPK and mTOR activator (LAMTOR) that anchors Rag GTPases to the lysosome, resulted in autolysosome accumulation, suggesting that RagGTPases regulate lysosomal acidification depend on their lysosomal localization. Knockdown of the CCT complex components attenuated the autophagic defects in Lamtor 4 RNAi. Our work highlights the interaction between CCT and v-ATPase in regulating lysosomal acidification.

Keywords: Drosophila melanogaster; Rag GTPases; V-ATPase assembly; autophagy; chaperonin containing tailless complex polypeptide 1

DOI: https://doi.org/10.1016/j.jbc.2025.110400

PLoS Genet. 2025 Jun 27. 21(6): e1011754

The transcription factors Tfeb and Tfe3 are required for survival and embryonic development of pancreas and liver in zebrafish.

Alberto Rissone, Martina La Spina, Erica Bresciani, Zulfeqhar A Syed, Christian A Combs, Martha Kirby, Abdel Elkahloun, Vicky Chen, Raman Sood, Shawn M Burgess, Rosa Puertollano.

The transcription factors TFEB and TFE3 modulate expression of lysosomal, autophagic, and metabolic genes to restore energy and cellular homeostasis in response to a variety of stress conditions. Since their role during vertebrate development is less characterized, we used CRISPR/Cas9 to deplete tfeb, tfe3a, and tfe3b in zebrafish. The simultaneous lack of these genes compromised embryo survival during early development, with an almost complete lethality of the larvae by 8-10 dpf. The knockout animals showed apoptosis in brain and retina and alterations in pancreas, liver, and gut. Exocrine pancreas presented the most severe defects, with accumulation of abnormal zymogen granules leading to acinar atrophy in embryos and pancreatitis-like phenotypes in adults; likely due to a block of the autophagy machinery implicated in removal of damaged granules. Knockout animals displayed increased susceptibility to oxidative and heat-shock stress. Our work reveals an essential role of Tfeb and Tfe3 in maintaining cellular and tissue homeostasis during development.

DOI: https://doi.org/10.1371/journal.pgen.1011754

Sci Rep. 2025 Jun 27. 15(1): 20347

Genetic screening of tuberous sclerosis complex in Sicily with a focus on neurological manifestations.

Andrea Domenico Praticò, Claudia Di Napoli, Stefania Salafia, Edoardo Dammino, Maria Piccione, Francesco Calì, Renato Scifo, Michele Vecchio, Andrea Zonta, Maria Bonsignore, Maurizio Elia, Manuela Lo Bianco, Agata Polizzi, Martino Ruggieri.

Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder characterized by widespread hamartomas and prominent neurological involvement. It results from pathogenic variants in the TSC1 or TSC2 genes, leading to hyperactivation of the mTOR pathway and consequent dysregulation of cell growth. These tumor suppressor genes encode hamartin and tuberin, proteins critical for regulating cell proliferation, neuronal excitability and synaptogenesis. In this retrospective study, we analyzed clinical, genetic and radiological features of 81 TSC patients from Sicily, focusing on genotype-phenotype correlations and intergroup comparisons. Pathogenic TSC2 variants were more common than pathogenic TSC1 variants (61.7% vs. 38.3%). Patients with pathogenic TSC2 variants tended to exhibit a higher frequency of weekly seizures, a higher prevalence of infantile spasms and hypsarrhythmia compared to those with pathogenic TSC1 variants, consistent with a more severe phenotype. Interestingly, TSC1 patients exhibited a higher incidence of radial bands, while TSC2 patients harbored a larger average size of tubers and subependymal nodules. Cognitive and behavioral disorders were similarly distributed, although TSC1 patients had higher rates of normal or borderline cognitive function, while TSC2 patients had more severe neuropsychiatric profiles compared to TSC1. To our knowledge, this is the first comprehensive TSC1 and TSC2 mutational analysis and genotype-phenotype correlation study carried out in a large cohort of Sicilian patients affected by TSC. Our findings contribute to regional and global data on TSC, emphasizing the utility of genotype-informed management strategies.

Keywords: TSC1 ; TSC2 ; Genotype/Phenotype; Seizures; Tuberous sclerosis complex

DOI: https://doi.org/10.1038/s41598-025-04718-6

Sci Transl Med. 2025 Jun 25. 17(804): eadq3852

Podocyte YAP and TAZ hyperactivation drives glomerular epithelial proliferative diseases in mice and humans.

Kidney diseases characterized by glomerular epithelial cell proliferation are rare but often devastating, frequently leading to progressive scarring and renal failure. Ranging from autoimmune-induced crescentic glomerulonephritis to HIV infection-induced collapsing glomerulopathy, these diseases are triggered by a wide variety of insults and have generally been thought of as different entities. Here, using immunostaining and spatial transcriptomics, we profiled human kidney biopsies collected from patients with two of these diseases, collapsing glomerulopathy and antineutrophil cytoplasmic antibody (ANCA) vasculitis-induced crescentic glomerulonephritis, to identify common disease-causing molecules. Although triggered by different insults, we identified abnormal hyperactivation of the transcription cofactors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in podocytes as a potential common driver of these diseases. To test this hypothesis, we genetically activated podocyte YAP and TAZ in cultured human cells and in mice by deleting the YAP and TAZ inhibitory large tumor suppressor kinases (LATSs). LATS deficiency in mouse podocytes induced a phenotypic transition in vitro, characterized by a highly distorted structure and an increase in matrix gene expression, mimicking many features of the podocytopathy seen in diseases characterized by glomerular epithelial proliferation. In mice, LATS-deficient podocytes orchestrated a profibrotic and pro-proliferative response in surrounding glomerular cells, a characteristic phenomenon of glomerular epithelial proliferative diseases. This response was attenuated when we also deleted podocyte YAP or TAZ in these mice. Together, our findings point to podocyte YAP-TAZ hyperactivation as a previously unrecognized and unifying driver of glomerular epithelial proliferative diseases.

DOI: https://doi.org/10.1126/scitranslmed.adq3852