bims-raghud 2024-10-27 papers

bims-raghud

Biomed News

on RagGTPases in human diseases

Issue of 2024‒10‒27
eleven papers selected by
Irene Sambri, TIGEM

Everolimus on cystic kidney disease burden reduction in pediatric tuberous sclerosis complex patients: a case series.
DYRK1A interacts with the tuberous sclerosis complex and promotes mTORC1 activity.
Gene therapy and kidney diseases.
Biomarkers of Kidney Disease Progression in ADPKD.
TFEB signaling promotes autophagic degradation of NLRP3 to attenuate neuroinflammation in diabetic encephalopathy.
Lysosomal Ca2+ release-facilitated TFEB nuclear translocation alleviates ischemic brain injury by attenuating autophagic/lysosomal dysfunction in neurons.
Multiple roles of mitochondrial autophagy receptor FUNDC1 in mitochondrial events and kidney disease.
Macrophages and autophagy: partners in crime.
Notch signaling regulates pulmonary fibrosis.
Lysosomal activity depends on TRPML1-mediated Ca2+ release coupled to incoming vesicle fusions.
Cyclophilin D plays a critical role in the survival of senescent cells.

BMC Nephrol. 2024 Oct 24. 25(1): 376

Everolimus on cystic kidney disease burden reduction in pediatric tuberous sclerosis complex patients: a case series.

Sumona Banerjee, Louis Richard Feldenberg.

  BACKGROUND: Tuberous Sclerosis complex (TSC) is a multisystemic neurocutaneous genetic condition with high rates of morbidity and mortality from subependymal giant cell astrocytoma (SEGA), renal angiomyolipoma, and renal cyst complications. Everolimus is an inhibitor for mTORC1 and is currently used to treat TSC for its main role in rapidly reducing SEGA volume and seizure burden, although mainly studied in the adult population. It has also been shown to stabilize estimated glomerular filtration rate and reduce renal angiomyolipoma size in the adult population.CASE PRESENTATION: This case report illustrates three pediatric patients placed on everolimus for SEGA and seizure control with incidental findings of the disappearance of or decreased burden of cystic kidney disease after everolimus therapy. In one patient, the cyst burden remained stable even after the cessation of everolimus while the SEGA resumed growth.
CONCLUSIONS: This report demonstrates the utility of everolimus in not only renal angiomyolipomas but also cystic kidney disease particularly in pediatric patients with a promising role in preserving renal function and preventing long term sequelae such as hematuria and hemorrhage from larger renal cysts especially if used early on in disease course.

Keywords:  Cystic kidney disease; Everolimus; Pediatrics; Renal angiomyolipoma; Tuberous sclerosis complex

DOI:  https://doi.org/10.1186/s12882-024-03743-3
Elife. 2024 Oct 22. pii: RP88318. [Epub ahead of print]12

DYRK1A interacts with the tuberous sclerosis complex and promotes mTORC1 activity.

Pinhua Wang, Sunayana Sarkar, Menghuan Zhang, Tingting Xiao, Fenhua Kong, Zhe Zhang, Deepa Balasubramanian, Nandan Jayaram, Sayantan Datta, Ruyu He, Ping Wu, Peng Chao, Ying Zhang, Michael Washburn, Laurence A Florens, Sonal Nagarkar-Jaiswal, Manish Jaiswal, Man Mohan.

  DYRK1A, a ubiquitously expressed kinase, is linked to the dominant intellectual developmental disorder, microcephaly, and Down syndrome in humans. It regulates numerous cellular processes such as cell cycle, vesicle trafficking, and microtubule assembly. DYRK1A is a critical regulator of organ growth; however, how it regulates organ growth is not fully understood. Here, we show that the knockdown of DYRK1A in mammalian cells results in reduced cell size, which depends on mTORC1. Using proteomic approaches, we found that DYRK1A interacts with the tuberous sclerosis complex (TSC) proteins, namely TSC1 and TSC2, which negatively regulate mTORC1 activation. Furthermore, we show that DYRK1A phosphorylates TSC2 at T1462, a modification known to inhibit TSC activity and promote mTORC1 activity. We also found that the reduced cell growth upon knockdown of DYRK1A can be rescued by overexpression of RHEB, an activator of mTORC1. Our findings suggest that DYRK1A inhibits TSC complex activity through inhibitory phosphorylation on TSC2, thereby promoting mTORC1 activity. Furthermore, using the Drosophila neuromuscular junction as a model, we show that the mnb, the fly homologs of DYRK1A, is rescued by RHEB overexpression, suggesting a conserved role of DYRK1A in TORC1 regulation.

Keywords:  D. melanogaster; DYRK1A; Drosophila melanogaster; biochemistry; cell biology; cell growth; chemical biology; microcephaly

DOI:  https://doi.org/10.7554/eLife.88318
Mol Ther Methods Clin Dev. 2024 Dec 12. 32(4): 101333

Gene therapy and kidney diseases.

Nadia Tavakolidakhrabadi, Wen Y Ding, Moin A Saleem, Gavin I Welsh, Carl May.

  Chronic kidney disease (CKD) poses a significant global health challenge, projected to become one of the leading causes of death by 2040. Current treatments primarily manage complications and slow progression, highlighting the urgent need for personalized therapies targeting the disease-causing genes. Our increased understanding of the underlying genomic changes that lead to kidney diseases coupled with recent successful gene therapies targeting specific kidney cells have turned gene therapy and genome editing into a promising therapeutic approach for treating kidney disease. This review paper reflects on different delivery routes and systems that can be exploited to target specific kidney cells and the ways that gene therapy can be used to improve kidney health.

Keywords:  gene therapy; kidney disease; nanodelivery systems; targeted gene delivery; viral vectors

DOI:  https://doi.org/10.1016/j.omtm.2024.101333
Kidney Int Rep. 2024 Oct;9(10): 2860-2882

Biomarkers of Kidney Disease Progression in ADPKD.

Ahmad Ghanem, Abdul Hamid Borghol, Fadi George Munairdjy Debeh, Stefan Paul, Bassel AlKhatib, Peter C Harris, Pranav S Garimella, Christian Hanna, Timothy L Kline, Neera K Dahl, Fouad T Chebib.

  Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disorder and the fourth leading cause of kidney failure (KF) in adults. Characterized by a reduction in glomerular filtration rate (GFR) and increased kidney size, ADPKD exhibits significant variability in progression, highlighting the urgent need for reliable and predictive biomarkers to optimize management and treatment approaches. This review explores the roles of diverse biomarkers-including clinical, genetic, molecular, and imaging biomarkers-in evaluating disease progression and customizing treatments for ADPKD. Clinical biomarkers such as biological sex, the predicting renal outcome in polycystic kidney disease (PROPKD) score, and body mass index are shown to correlate with disease severity and progression. Genetic profiling, particularly distinguishing between truncating and non-truncating pathogenic variants in the PKD1 gene, refines risk assessment and prognostic precision. Advancements in imaging significantly enhance our ability to assess disease severity. Height-adjusted total kidney volume (htTKV) and the Mayo imaging classification (MIC) are foundational, whereas newer imaging biomarkers, including texture analysis, total cyst number (TCN), cyst-parenchyma surface area (CPSA), total cyst volume (TCV), and cystic index, focus on detailed cyst characteristics to offer deeper insights. Molecular biomarkers (including serum and urinary markers) shed light on potential therapeutic targets that could predict disease trajectory. Despite these advancements, there is a pressing need for the development of response biomarkers in both the adult and pediatric populations, which can evaluate the biological efficacy of treatments. The holistic evaluation of these biomarkers not only deepens our understanding of kidney disease progression in ADPKD, but it also paves the way for personalized treatment strategies aiming to significantly improve patient outcomes.

Keywords:  ADPKD; biomarkers; polycystic kidney disease; predictive model; prognosis; total kidney volume

DOI:  https://doi.org/10.1016/j.ekir.2024.07.012
Am J Physiol Cell Physiol. 2024 Oct 22.

TFEB signaling promotes autophagic degradation of NLRP3 to attenuate neuroinflammation in diabetic encephalopathy.

Yijia Lin, Lizhen Cheng, Yixin Chen, Wei Li, Qihao Guo, Ya Miao.

  Diabetic encephalopathy (DE), a neurological complication of diabetes mellitus, has an unclear etiology. Shreds of evidence show that the Nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome-induced neuroinflammation and transcription factor EB (TFEB)-mediated autophagy impairment may take part in DE development. The crosstalk between these two pathways and their contribution to DE remains to be explored. A mouse model of type 2 diabetes mellitus (T2DM) exhibiting cognitive dysfunction was created, along with high glucose (HG) cultured BV2 cells. Following, 3-methyladenine (3-MA) and rapamycin were utilized to modulate autophagy. To evaluate the potential therapeutic benefits of TFEB in DE, we overexpressed and knocked down TFEB in both mice and cells. Autophagy impairment and NLRP3 inflammasome activation were noticed in T2DM mice and HG-cultured BV2 cells. The inflammatory response caused by NLRP3 inflammasome activation was decreased by rapamycin-induced autophagy enhancement, while 3-MA treatment further deteriorated it. Nuclear translocation and expression of TFEB were hampered in HG-cultured BV2 cells and T2DM mice. Exogenous TFEB overexpression boosted NLRP3 degradation via autophagy, which in turn alleviated microglial activation as well as ameliorated cognitive deficits and neuronal damage. Additionally, TFEB knockdown exacerbated neuroinflammation by decreasing autophagy-mediated NLRP3 degradation. Our findings have unraveled the pathogenesis of a previously underappreciated disease, implying that the activation of NLRP3 inflammasome and impairment of autophagy in microglia are significant etiological factors in the DE. The TFEB-mediated autophagy pathway can reduce neuroinflammation by enhancing NLRP3 degradation. This could potentially serve as a viable and innovative treatment approach for DE.

Keywords:  Autophagy; Diabetic encephalopathy; Microglia; NLRP3; TFEB

DOI:  https://doi.org/10.1152/ajpcell.00322.2024
Sci Rep. 2024 10 22. 14(1): 24836

Lysosomal Ca2+ release-facilitated TFEB nuclear translocation alleviates ischemic brain injury by attenuating autophagic/lysosomal dysfunction in neurons.

Qian Lei, Xuemei Chen, Yajie Xiong, Shangdan Li, Jiaqian Wang, Hongyun He, Yihao Deng.

  Neuronal death was frequently driven by autophagic/lysosomal dysfunction after ischemic stroke, whereas how to restore the impaired autophagic flux remained elusive. Autophagic/lysosomal signaling could be augmented after transcription factor EB (TFEB) nuclear translocation, which was facilitated by its dephosphorylation. A key TFEB dephosphorylase was calcineurin (CaN), whose activity was drastically regulated by cytosolic calcium ion concentration ([Ca2+]) controlled by lysosomal Ca2+ channel-like protein of TRPML1. Our research shows that ML-SA1, an agonist of the TRPML1 channel, significantly enhanced the lysosomal Ca2+ release and the CaN expression in penumbric neurons, subsequently promoted TFEB nuclear translocation, and greatly reversed autophagy/lysosome dysfunction. Moreover, ML-SA1 treatment significantly reduced neuronal loss, infarct size, and neurological deficits. By contrast, ML-SI3, an inhibitor of TRPML1, inhibited the lysosomal Ca2+ release conversely, aggravated the impairment of autophagic flux and consequentially exacerbated brain stroke lesion. These studies suggest that TRPML1 elevation alleviates ischemic brain injury by restoring autophagic/lysosomal dysfunction via Lysosomal Ca2+ release-facilitated TFEB nuclear translocation in neurons.

Keywords:  Autophagic/lysosomal dysfunction; Ischemic stroke; Lysosomal Ca2+ ; Neuroprotection; TFEB; TRPML1

DOI:  https://doi.org/10.1038/s41598-024-75802-6
Front Cell Dev Biol. 2024 ;12 1453365

Multiple roles of mitochondrial autophagy receptor FUNDC1 in mitochondrial events and kidney disease.

Kaiqing Li, Xue Xia, Ying Tong.

  This article reviews the latest research progress on the role of mitochondrial autophagy receptor FUN14 domain containing 1 (FUNDC1) in mitochondrial events and kidney disease. FUNDC1 is a protein located in the outer membrane of mitochondria, which maintains the function and quality of mitochondria by regulating mitochondrial autophagy, that is, the selective degradation process of mitochondria. The structural characteristics of FUNDC1 enable it to respond to intracellular signal changes and regulate the activity of mitochondrial autophagy through phosphorylation and dephosphorylation. During phosphorylation, unc-51-like kinase 1 (ULK1) promotes the activation of mitophagy by phosphorylating Ser17 of FUNDC1. In contrast, Src and CK2 kinases inhibit the interaction between FUNDC1 and LC3 by phosphorylating Tyr18 and Ser13, thereby inhibiting mitophagy. During dephosphorylation, PGAM5 phosphatase enhances the interaction between FUNDC1 and LC3 by dephosphorylating Ser13, thereby activating mitophagy. BCL2L1 inhibits the activity of PGAM5 by interacting with PGAM5, thereby preventing the dephosphorylation of FUNDC1 and inhibiting mitophagy. FUNDC1 plays an important role in mitochondrial events, participating in mitochondrial fission, maintaining the homeostasis of iron and proteins in mitochondrial matrix, and mediating crosstalk between mitochondria, endoplasmic reticulum and lysosomes, which have important effects on cell energy metabolism and programmed death. In the aspect of kidney disease, the abnormal function of FUNDC1 is closely related to the occurrence and development of many diseases. In acute kidney injury (AKI), cardiorenal syndrome (CRS), diabetic nephropathy (DN), chronic kidney disease (CKD) ,renal fibrosis (RF) and renal anemia, FUNDC1-mediated imbalance of mitophagy may be one of the key factors in disease progression. Therefore, in-depth study of the regulatory mechanism and function of FUNDC1 is of great significance for understanding the pathogenesis of renal disease and developing new treatment strategies.

Keywords:  FUNDC1; dephosphorylation; kidney disease; mitochondrial autophagy; phosphorylation

DOI:  https://doi.org/10.3389/fcell.2024.1453365
FEBS J. 2024 Oct 22.

Macrophages and autophagy: partners in crime.

Alessandra Vitaliti, Alessio Reggio, Alessandro Palma.

  Macrophages and autophagy are intricately linked, both playing vital roles in maintaining homeostasis and responding to disease. Macrophages, known for their 'eating' function, rely on a sophisticated digestion system to process a variety of targets, from apoptotic cells to pathogens. The connection between macrophages and autophagy is established early in their development, influencing both differentiation and mature functions. Autophagy regulates essential immune functions, such as inflammation control, pathogen clearance, and antigen presentation, linking innate and adaptive immunity. Moreover, it modulates cytokine production, ensuring a balanced inflammatory response that prevents excessive tissue damage. Autophagy also plays a critical role in macrophage polarization, influencing their shift between pro-inflammatory and anti-inflammatory states. This review explores the role of autophagy in macrophages, emphasizing its impact across various tissues and pathological conditions, and detailing the cellular and molecular mechanisms by which autophagy shapes macrophage function.

Keywords:  autophagy; immunity; lysosome; macrophages; phagocytes

DOI:  https://doi.org/10.1111/febs.17305
Front Cell Dev Biol. 2024 ;12 1450038

Notch signaling regulates pulmonary fibrosis.

Xinyue Zhang, Zhihao Xu, Qi Chen, Zhimin Zhou.

  Pulmonary fibrosis is a progressive interstitial lung disease associated with aging. The pathogenesis of pulmonary fibrosis remains unclear, however, alveolar epithelial cell injury, myofibroblast activation, and extracellular matrix (ECM) accumulation are recognized as key contributors. Moreover, recent studies have implicated cellular senescence, endothelial-mesenchymal transition (EndMT), and epigenetic modifications in the pathogenesis of fibrotic diseases. Various signaling pathways regulate pulmonary fibrosis, including the TGF-β, Notch, Wnt, Hedgehog, and mTOR pathways. Among these, the TGF-β pathway is extensively studied, while the Notch pathway has emerged as a recent research focus. The Notch pathway influences the fibrotic process by modulating immune cell differentiation (e.g., macrophages, lymphocytes), inhibiting autophagy, and promoting interstitial transformation. Consequently, inhibiting Notch signaling represents a promising approach to mitigating pulmonary fibrosis. In this review, we discuss the role of Notch signaling pathway in pulmonary fibrosis, aiming to offer insights for future therapeutic investigations.

Keywords:  autophagy; macrophage polarization; mesenchymal transformation; notch; pulmonary fibrosis

DOI:  https://doi.org/10.3389/fcell.2024.1450038
J Biol Chem. 2024 Oct 19. pii: S0021-9258(24)02413-X. [Epub ahead of print] 107911

Lysosomal activity depends on TRPML1-mediated Ca2+ release coupled to incoming vesicle fusions.

Arindam Bhattacharjee, Hussein Abuammar, Gábor Juhász.

  The lysosomal cation channel TRPML1/MCOLN1 facilitates autophagic degradation during amino acid starvation based on studies involving long-term TRMPL1 modulation. Here we show that lysosomal activation (more acidic pH and higher hydrolase activity) depends on incoming vesicle fusions. We identify an immediate, calcium-dependent role of TRPML1 in lysosomal activation through promoting autophagosome-lysosome fusions and lysosome acidification within 10-20 minutes of its pharmacological activation. Lysosomes also become more fusion competent upon TRPML1 activation via increased transport of lysosomal SNARE proteins syntaxin 7 and VAMP7 by SNARE carrier vesicles. We find that incoming vesicle fusion is a prerequisite for lysosomal Ca2+ efflux that leads to acidification and hydrolytic enzyme activation. Physiologically, the first vesicle fusions likely trigger generation of the phospholipid PI(3,5)P2 that activates TRPML1, and allosteric TRPML1 activation in the absence of PI(3,5)P2 restores autophagosome-lysosome fusion and rescues abnormal SNARE sequestration within lysosomes. We thus identify a prompt role of TRPML1-mediated calcium signaling in lysosomal fusions, activation, and SNARE trafficking.

Keywords:  SNARE proteins; autophagy; ion channel; lysosomal acidification; membrane fusion

DOI:  https://doi.org/10.1016/j.jbc.2024.107911
EMBO J. 2024 Oct 24.

Cyclophilin D plays a critical role in the survival of senescent cells.

Margherita Protasoni, Vanessa López-Polo, Camille Stephan-Otto Attolini, Julian Brandariz, Nicolas Herranz, Joaquin Mateo, Sergio Ruiz, Oscar Fernandez-Capetillo, Marta Kovatcheva, Manuel Serrano.

  Senescent cells play a causative role in many diseases, and their elimination is a promising therapeutic strategy. Here, through a genome-wide CRISPR/Cas9 screen, we identify the gene PPIF, encoding the mitochondrial protein cyclophilin D (CypD), as a novel senolytic target. Cyclophilin D promotes the transient opening of the mitochondrial permeability transition pore (mPTP), which serves as a failsafe mechanism for calcium efflux. We show that senescent cells exhibit a high frequency of transient CypD/mPTP opening events, known as 'flickering'. Inhibition of CypD using genetic or pharmacologic tools, including cyclosporin A, leads to the toxic accumulation of mitochondrial Ca2+ and the death of senescent cells. Genetic or pharmacological inhibition of NCLX, another mitochondrial calcium efflux channel, also leads to senolysis, while inhibition of the main Ca2+ influx channel, MCU, prevents senolysis induced by CypD inhibition. We conclude that senescent cells are highly vulnerable to elevated mitochondrial Ca2+ ions, and that transient CypD/mPTP opening is a critical adaptation mechanism for the survival of senescent cells.

Keywords:  Cellular Senescence; Cyclophilin D; Mitochondria; Senolytic Therapy; mPTP Flickering

DOI:  https://doi.org/10.1038/s44318-024-00259-2