bims-raghud 2025-05-18 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2025–05–18
six papers selected by
Irene Sambri, TIGEM

TORC1 autonomously controls its spatial partitioning via the Rag GTPase tether Tco89.
Enhanced SIRT1-TFEB Interaction Promotes Lysosome Biogenesis and Autophagy by Reducing TFEB Acetylation: Revealing the Enterotoxicity Disparity of Deoxynivalenol and T-2 Toxin.
The anti-atherosclerosis effect and molecular mechanism of AMPKα1 by polarizing monocytes to an M2 phenotype via cell-intrinsic lysosomal lipolysis.
Decoding the dual role of autophagy in cancer through transcriptional and epigenetic regulation.
Mechanistic strategies for secondary prevention of developmental and epileptic encephalopathy in children with tuberous sclerosis complex.
mTORopathies in Epilepsy and Neurodevelopmental Disorders: The Future of Therapeutics and the Role of Gene Editing.

Cell Rep. 2025 May 12. pii: S2211-1247(25)00454-1. [Epub ahead of print]44(5): 115683

TORC1 autonomously controls its spatial partitioning via the Rag GTPase tether Tco89.

Raffaele Nicastro, Marie-Pierre Péli-Gulli, Marco Caligaris, Malika Jaquenoud, Ladislav Dokládal, Josephine Alba, Farida Tripodi, Benjamin Pillet, Melanie Brunner, Michael Stumpe, Kenji Muneshige, Riko Hatakeyama, Jörn Dengjel, Claudio De Virgilio.

  The eukaryotic target of rapamycin complex 1 (TORC1) kinase is a homeostatic regulator of growth, integrating nutritional cues at the endolysosomal compartment. Amino acids activate mammalian TORC1 (mTORC1) through the Rag GTPases that recruit it to lysosomes via a short domain within the mTORC1 subunit Raptor. Intriguingly, this "Raptor claw" domain is absent in Kog1, the Raptor ortholog in yeast. Instead, as we show here, yeast utilizes the fungal-specific Tco89 to tether TORC1 to active Rag GTPases. This interaction enables TORC1 to precisely calibrate the activity of the S6K1-related effector kinase Sch9 in response to amino acid availability. TORC1 stabilizes Tco89 by phosphorylation, and its inactivation causes swift Tco89 proteolysis, provoking a redistribution of TORC1 from the vacuole to signaling endosomes and its spatial separation from Sch9. Thus, TORC1 not only operates in spatially distinct subcellular pools but also controls its own quantitative distribution between these pools to economize energy resources under fluctuating nutrient conditions.

Keywords:  CP: Cell biology; CP: Molecular biology; Rag GTPases; TORC1; Tco89; amino acid signaling; growth control; target of rapamycin complex 1

DOI:  https://doi.org/10.1016/j.celrep.2025.115683
J Agric Food Chem. 2025 May 15.

Enhanced SIRT1-TFEB Interaction Promotes Lysosome Biogenesis and Autophagy by Reducing TFEB Acetylation: Revealing the Enterotoxicity Disparity of Deoxynivalenol and T-2 Toxin.

Qiang Xu, Ruqin Lin, Tianqing Jiang, Luyu Deng, Yuting Wu, Qianqian Yuan, Xueying Qi, Peiqiang Mu, Jun Jiang, Yiqun Deng, Jikai Wen.

  Multiple environmental factors contribute to digestive system damage caused by food contamination in both humans and animals. Mycotoxins, such as deoxynivalenol (DON) and T-2 toxin, have emerged as the most significant factors due to their extensive contamination and difficulty in removal. Transcription factor EB (TFEB) serves as a crucial transcriptional regulator governing lysosomal biogenesis and autophagy, a lysosomal-driven degradation system that safeguards cells against harmful stressors. However, little is known about whether the post-translational modification of TFEB affects autophagy activity, which could explain the toxicity disparity between DON and T-2 toxin. Here, we discovered that T-2 toxin induces excessive autophagy by significantly reducing TFEB acetylation, whereas DON surprisingly inhibits autophagy activity via maintaining high TFEB acetylation, which impairs lysosomal biogenesis, thereby boosting their respective toxicity. Mechanically, the T-2 toxin decreases TFEB acetylation via enhanced SIRT1-TFEB interaction and SIRT1 deacetylase activity, while DON maintains high TFEB acetylation by reversing the process. Together, our study revealed that the acetylation state of TFEB mediated by SIRT1 alters autophagy phenotypes in intestinal cells, shedding light on the various toxicological mechanisms and an important target of DON and T-2 toxin.

Keywords:  SIRT1; T-2 toxin; TFEB; acetylation; autophagy; deoxynivalenol; lysosome

DOI:  https://doi.org/10.1021/acs.jafc.5c01854
Cardiovasc Pathol. 2025 May 10. pii: S1054-8807(25)00027-4. [Epub ahead of print] 107742

The anti-atherosclerosis effect and molecular mechanism of AMPKα1 by polarizing monocytes to an M2 phenotype via cell-intrinsic lysosomal lipolysis.

Jing Wang, Yahui Zhang, Caixing Cao, Jiale Hua, Li Xing, Changxin Wu.

  Regulating the differentiation of monocytes into M2 macrophages can promote the regression of Atherosclerosis (AS) plaque. However, the key molecules regulating the differentiation of monocytes to M2 are unknown. In this study, we reported that adenosine-activated protein kinase α1 (AMPKα1) plays an anti-AS role by polarizing monocytes to an M2 phenotype via promoting fatty acid oxidation (FAO). AMPKα1 enhances the decomposition of cholesterol esters by increasing lysosomal acid lipase expression to provide fatty acids for FAO. Furthermore, AMPKα1 can induce lysosomal biogenesis and enhance lipolysis by promoting the transcription factor EB (TFEB) expression and facilitating TFEB nuclear translocation. In conclusion, AMPKα1 enhances the decomposition of cholesterol esters by increasing lysosomal acid lipase expression to produce fatty acids, which may represent a mechanism to promote FAO and inflammatory monocytes differentiation towards M2 phenotype.

Keywords:  M2 macrophage; adenosine-activated protein kinase α1; atherosclerosis; lysosomal acid lipase; lysosome; monocytes; transcription factor EB

DOI:  https://doi.org/10.1016/j.carpath.2025.107742
FEBS Lett. 2025 May 09.

Decoding the dual role of autophagy in cancer through transcriptional and epigenetic regulation.

Young Suk Yu, Ik Soo Kim, Sung Hee Baek.

  Autophagy is a conserved catabolic process that is essential for maintaining cellular homeostasis by degrading and recycling damaged organelles and misfolded proteins. In cancer, autophagy exhibits a context-dependent dual role: In early stages, autophagy acts as a tumor suppressor by preserving genomic integrity and limiting oxidative stress. In advanced stages, autophagy supports tumor progression by facilitating metabolic adaptation, therapy resistance, immune evasion, and metastasis. This review highlights the molecular mechanisms underlying this dual function and focuses on the transcriptional and epigenetic regulation of autophagy in cancer cells. Key transcription factors, including the MiT/TFE family, FOXO family, and p53, as well as additional regulators, are discussed in the context of stress-responsive pathways mediated by mTORC1 and AMPK. A deeper understanding of the transcriptional and epigenetic regulation of autophagy in cancer is crucial for developing context-specific therapeutic strategies to either promote or inhibit autophagy depending on the cancer stage, thereby improving clinical outcomes in cancer treatment.

Keywords:  autophagy; cancer; epigenetics; lysosome; transcription factor

DOI:  https://doi.org/10.1002/1873-3468.70060
EBioMedicine. 2025 May 13. pii: S2352-3964(25)00184-7. [Epub ahead of print]116 105740

Mechanistic strategies for secondary prevention of developmental and epileptic encephalopathy in children with tuberous sclerosis complex.

Nicola Specchio, Valentina Di Micco, Mirte Scheper, Eleonora Aronica, Paolo Curatolo.

  Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by pathogenic variants in TSC1 or TSC2, leading to mTOR pathway dysregulation and a spectrum of systemic and neurological manifestations. Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder frequently associated with early-onset, drug-resistant epilepsy, intellectual disability, and autism spectrum disorder-collectively known as TSC-associated developmental and epileptic encephalopathy (DEE). Advances in prenatal diagnostics and biomarker research now enable presymptomatic identification of high-risk infants. This review aims to synthesize current evidence on biomarker-informed, mechanism-based strategies for secondary prevention of DEE in TSC, offering a framework for personalized early interventions. Biomarkers, such as interictal epileptiform discharges, pathogenic TSC2 variants, and advanced neuroimaging metrics, predict epilepsy risk and neurodevelopmental trajectories. Preventive approaches include early initiation of vigabatrin and mTOR inhibitors, which show potential in reducing epilepsy severity and improving outcomes. Emerging strategies, including gene therapy, multi-omic profiling, and environmental enrichment, offer promise for disease modification. By linking predictive biomarkers to disease-modifying strategies, this review outlines a proactive and personalised approach to prevent or mitigate TSC-associated DEE. These insights help advance clinical decision-making and promote a shift toward precision prevention in paediatric epilepsy.

Keywords:  Biomarkers and precision medicine; Developmental and epileptic encephalopathy (DEE); Presymptomatic intervention; Tuberous sclerosis complex (TSC); mTOR pathway dysregulation

DOI:  https://doi.org/10.1016/j.ebiom.2025.105740
Cells. 2025 Apr 30. pii: 662. [Epub ahead of print]14(9):

mTORopathies in Epilepsy and Neurodevelopmental Disorders: The Future of Therapeutics and the Role of Gene Editing.

Marina Ottmann Boff, Fernando Antônio Costa Xavier, Fernando Mendonça Diz, Júlia Budelon Gonçalves, Laura Meireles Ferreira, Jean Zambeli, Douglas Bottega Pazzin, Thales Thor Ramos Previato, Helena Scartassini Erwig, João Ismael Budelon Gonçalves, Fernanda Thays Konat Bruzzo, Daniel Marinowic, Jaderson Costa da Costa, Gabriele Zanirati.

  mTORopathies represent a group of neurodevelopmental disorders linked to dysregulated mTOR signaling, resulting in conditions such as tuberous sclerosis complex, focal cortical dysplasia, hemimegalencephaly, and Smith-Kingsmore Syndrome. These disorders often manifest with epilepsy, cognitive impairments, and, in some cases, structural brain anomalies. The mTOR pathway, a central regulator of cell growth and metabolism, plays a crucial role in brain development, where its hyperactivation leads to abnormal neuroplasticity, tumor formation, and heightened neuronal excitability. Current treatments primarily rely on mTOR inhibitors, such as rapamycin, which reduce seizure frequency and tumor size but fail to address underlying genetic causes. Advances in gene editing, particularly via CRISPR/Cas9, offer promising avenues for precision therapies targeting the genetic mutations driving mTORopathies. New delivery systems, including viral and non-viral vectors, aim to enhance the specificity and efficacy of these therapies, potentially transforming the management of these disorders. While gene editing holds curative potential, challenges remain concerning delivery, long-term safety, and ethical considerations. Continued research into mTOR mechanisms and innovative gene therapies may pave the way for transformative, personalized treatments for patients affected by these complex neurodevelopmental conditions.

Keywords:  CRISPR/Cas9; epilepsy; exosomes; extracellular vesicles; gene therapy; mTOR; mTORopathy

DOI:  https://doi.org/10.3390/cells14090662