bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2026–02–15
six papers selected by
Irene Sambri, TIGEM
  1. Autophagy in kidney physiology: from cellular quality control to organ metabolism.
  2. Central Role of MITF/TFE Family Transcription Factors in Diverse Clear and Granular Cell Tumors.
  3. Tuberous sclerosis complex with multisystem involvement: A case report.
  4. TSC-associated microglial hyperactivity: enhanced calcium signaling, metabolism, and phagocytosis.
  5. AMPK promotes TFEB transcriptional activity through dephosphorylation at both MTORC1-dependent and -independent sites.
  6. Microglia TFEB activation attenuates Alzheimer's disease pathology by enhancing autophagy-lysosomal function.
  1. Autophagy Rep. 2026 ;5(1): 2622228
    Autophagy in kidney physiology: from cellular quality control to organ metabolism.
    Takeshi Yamamoto, Satoshi Minami, Yoshitaka Isaka.
      Autophagy is a cellular process that maintains kidney physiology by recycling intracellular components to preserve homeostasis. In the kidney, autophagy supports energy metabolism and integrity across multiple cell types. Its regulation is tightly governed by nutrient availability, hormonal cues, and oxygen levels, primarily through signaling pathways such as mechanistic target of rapamycin kinase (mTOR), AMP-activated protein kinase (AMPK), and transcription factor EB (TFEB). Under physiological conditions, autophagy is dynamically regulated to meet metabolic demands. However, aging, obesity, and metabolic stress impair lysosomal function, leading to a pathological state termed autophagic stagnation, in which autophagosomes accumulate but degradative flux is compromised. Rather than being uniformly protective, this stagnation promotes cellular damage and contributes to kidney disease progression. Notably, autophagic stagnation in proximal tubular epithelial cells (PTECs) contributes to acute kidney injury (AKI)-to-chronic kidney disease (CKD) transition and exacerbates lipotoxicity in obesity-related kidney disease. Recent studies highlight the importance of transcriptional regulators - including TFEB and MondoA - in maintaining autophagic activity and mitochondrial homeostasis. Therapeutic strategies aimed at restoring autophagic flux - pharmacologically or through lifestyle interventions such as caloric restriction - hold promise for preserving kidney function. Deeper understanding of cell type - specific autophagy regulation will be critical for developing targeted and context-specific therapies.
    Keywords:  Mitophagy; Rubicon; autophagic stagnation; fibroblast growth factor 21 (FGF21); lipophagy; lysophagy; proximal tubular epithelial cells (PTECs)
    DOI:  https://doi.org/10.1080/27694127.2026.2622228
  2. Am J Pathol. 2026 Feb 06. pii: S0002-9440(26)00035-0. [Epub ahead of print]
    Central Role of MITF/TFE Family Transcription Factors in Diverse Clear and Granular Cell Tumors.
    Dale Davis, John Hanna.
      Clear cell morphology is an uncommon finding in human tumors and reflects the distinctive appearance of the cytoplasm under standard histopathologic examination. Granular cell morphology appears to be a closely related phenomenon and reflects an abundant eosinophilic cytoplasm. Accumulating evidence suggests a central role for the MITF/TFE family of transcription factors in diverse clear cell and granular cell neoplasms. A principal function of these transcription factors concerns cytoplasmic organellar biogenesis: TFEB is the master regulator of lysosome biogenesis while MITF controls the biogenesis of lysosome-related organelles known as melanosomes which are responsible for melanin pigment production. Here we review the role of MITF/TFE pathway activation in a variety of benign and malignant tumors, with an emphasis on the diverse oncogenic mechanisms that activate this pathway and the resulting altered cell biology that contributes to the distinctive histomorphologic features.
    Keywords:  MITF; TFE3; TFEB; clear cell; lysosome; melanocytic; melanosome
    DOI:  https://doi.org/10.1016/j.ajpath.2026.01.010
  3. J Int Med Res. 2026 Feb;54(2): 3000605261417081
    Tuberous sclerosis complex with multisystem involvement: A case report.
    Haoran Chen, Minhua Shi, Yong Yu, Zengli Zhang, Ziyan Du.
      Tuberous sclerosis complex is a rare, autosomal dominant disorder caused by pathogenic variants in the tuberous sclerosis complex 1 or tuberous sclerosis complex 2 genes, leading to constitutive activation of the mammalian target of rapamycin pathway and abnormal cell growth. Tuberous sclerosis complex is characterized by benign hamartomas affecting multiple organs, most commonly the brain, skin, kidneys, heart, and lungs. Clinical manifestations vary depending on the organs involved and disease severity. We report the case of a Chinese woman in her mid-30s who presented with progressive dyspnea. Her medical history included hypertension, intellectual disability, seizures, left nephron-sparing enucleation for renal angiomyolipoma, and hysterectomy for uterine smooth muscle tumors. Physical examination revealed classic features of tuberous sclerosis complex, including facial angiofibromas and periungual fibromas. Imaging demonstrated a right-sided pleural effusion. Thoracoabdominal imaging showed pulmonary lymphangioleiomyomatosis and bilateral renal angiomyolipomas with hemorrhage. Genetic testing identified three pathogenic variants in the tuberous sclerosis complex 2 gene. A multidisciplinary team confirmed the diagnosis of tuberous sclerosis complex with multisystem involvement. This case highlights the multisystem heterogeneity of tuberous sclerosis complex and underscores the importance of an interdisciplinary approach to diagnosis and management.
    Keywords:  Tuberous sclerosis complex; lymphangioleiomyomatosis; multisystem involvement; pleural effusion; tuberous sclerosis complex 2 gene
    DOI:  https://doi.org/10.1177/03000605261417081
  4. Acta Neuropathol. 2026 Feb 13. 151(1): 16
    TSC-associated microglial hyperactivity: enhanced calcium signaling, metabolism, and phagocytosis.
    Rozemarijn S Kalf, Mark J Luinenburg, Giulia Dematteis, Mirte Scheper, Jasper J Anink, Giulia Cavallo, Andrea Mattarei, Wim Van Hecke, Angelika Mühlebner, Laura Tapella, James D Mills, Dmitry Lim, Eleonora Aronica.
      Tuberous sclerosis complex (TSC) is a multisystem genetic disorder with prominent neurological manifestations, most notably epilepsy, and is frequently accompanied by a wide range of neuropsychiatric comorbidities. Hyperactivation of the mechanistic target of rapamycin (mTOR) pathway plays a central role in TSC pathology, disrupting both general brain development and specific molecular processes such as metabolism. While much attention has focused on neurons and astrocytes in these TSC-related alterations, the contribution of microglia remains relatively underexplored. In this study, we first analysed the transcriptomic profiles from resected TSC brain tissue and identified evidence of calcium (Ca2+) dysregulation in TSC microglia. In order to investigate the functional consequences, we then examined induced pluripotent stem cell (iPSC) derived microglia-like (iMGL) cells from TSC patients. Our findings reveal that these iMGL cells displayed markedly altered Ca2⁺ signalling, characterized by impaired store-operated calcium entry (SOCE) and an increase in mitochondrial Ca2⁺ uptake. These changes are accompanied by elevated mitochondrial respiratory activity, suggesting a shift in metabolic state. In addition, TSC iMGL cells displayed increased phagocytic activity and an altered inflammatory responsiveness, consistent with a dysregulated microglial activation state. Supporting these functional alterations in iMGL cells, transcriptomic analysis of TSC brain tissue revealed upregulation of several genes associated with lipid metabolism, phagocytosis, and innate immune activation, with partial overlap with stage 2 disease-associated microglia (DAM)-like programs. Together these findings suggest that microglial dysfunction may represent a relevant component of TSC pathophysiology.
    Keywords:  Calcium signalling; Epilepsy; Microglia; Phagocytosis; Tuberous sclerosis complex
    DOI:  https://doi.org/10.1007/s00401-026-02986-8
  5. Autophagy. 2026 Feb 09.
    AMPK promotes TFEB transcriptional activity through dephosphorylation at both MTORC1-dependent and -independent sites.
    Florentina Negoita, Conchita Fraguas Bringas, Kristina Hellberg, Katarzyna M Luda, Hongling Liu, Zhiyuan Li, Joyceline Cuenco, Jin-Feng Zhao, Gajanan Sathe, Ian G Ganley, Gopal P Sapkota, Kei Sakamoto.
      TFEB (transcription factor EB) is a critical regulator of lysosomal biogenesis, macroautophagy/autophagy and energy homeostasis through controlling expression of genes belonging to the coordinated lysosomal expression and regulation network. AMP-activated protein kinase (AMPK) has been reported to phosphorylate TFEB at three conserved C-terminal serine residues (S466, S467, S469) and these phosphorylation events were reported to be essential for transcriptional activation of TFEB. In sharp contrast to this proposition, we demonstrate that AMPK activation leads to the dephosphorylation of the C-terminal sites. We show that a synthetic peptide encompassing the C-terminal serine residues of TFEB is a poor substrate of AMPK in vitro. Treatment of cells with an AMPK activator (MK-8722), glucose deprivation or MTOR inhibitor (torin1) robustly dephosphorylated TFEB not only at the MTORC1-targeted N-terminal serine sites, but also at the C-terminal sites. Loss of function of AMPK abrogated MK-8722- but not torin1-induced dephosphorylation and induction of the TFEB target genes.
    Keywords:  BAY-3827; MK-8722; MTOR; TFE3; coordinated lysosomal expression and regulation; reversible phosphorylation
    DOI:  https://doi.org/10.1080/15548627.2026.2629720
  6. J Neuroinflammation. 2026 Feb 11.
    Microglia TFEB activation attenuates Alzheimer's disease pathology by enhancing autophagy-lysosomal function.
    Yeji Kim, Tae-Young Ha, Oksana Kondaurova, Myung-Shik Lee, Keun-A Chang.
      Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neuroinflammation, synaptic dysfunction, and cognitive decline. Impairment of microglial autophagy-lysosomal pathway (ALP) is increasingly recognized as a key driver of the disease progression. Transcription factor EB (TFEB), a master regulator of ALP, has emerged as a promising therapeutic target; however, its specific role in microglia remains unclear. Here, we aimed to determine the therapeutic effects of microglial TFEB expression in AD pathogenesis. We established a tamoxifen-inducible, microglia-specific TFEB-overexpressing 5xFAD mouse line (5xTFEB) and conducted behavioural testing, histopathology and biochemical analyses, live-cell imaging of Aβ phagocytosis, and bulk RNA sequencing. Differential gene expressions were analysed, and inflammasome activation was evaluated. Microglial TFEB overexpression restored ALP function, promoted phagolysosomal clearance of oligomeric Aβ, and reduced the amyloid burden in the cortex, hippocampus, and entorhinal cortex of the 5xFAD mice. These changes rescued memory deficits in both male and female 5xTFEB mice. Transcriptomic profiling revealed upregulation of ALP and downregulation of inflammatory signalling. Additionally, inflammasome activation was attenuated in 5xTFEB mice. Targeted TFEB activation in microglia reprograms degradative and immune pathways, enhancing Aβ clearance while alleviating neuroinflammation and cognitive impairment in AD. Overall, microglial TFEB modulation is a promising cell-type-specific therapeutic strategy for AD and related neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; Amyloid beta; Autophagy-lysosomal pathway; Microglia; Neuroinflammation; TFEB
    DOI:  https://doi.org/10.1186/s12974-026-03728-z
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