bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2025–01–26
eleven papers selected by
Irene Sambri, TIGEM
  1. Induction of lysosome biogenesis is a novel function of the CGAS-STING1 pathway.
  2. Caloric restriction exacerbates renal post-ischemic injury and fibrosis by modulating mTORC1 signaling and autophagy.
  3. Splice age: mTORC1-mediated RNA splicing in metabolism and ageing.
  4. mTor limits autophagy to facilitate cell volume expansion and rapid wound repair in Drosophila embryos.
  5. Cryo-EM reveals cholesterol binding in the lysosomal GPCR-like protein LYCHOS.
  6. N-Cadherin promotes cardiac regeneration by potentiating pro-mitotic β-Catenin signaling in cardiomyocytes.
  7. mTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.
  8. Advances in cardiac organoid research: implications for cardiovascular disease treatment.
  9. Mitochondrial quality control: Biochemical mechanism of cardiovascular disease.
  10. KDIGO 2025 clinical practice guideline for the evaluation, management, and treatment of autosomal dominant polycystic kidney disease (ADPKD): executive summary.
  11. Advances in CRISPR-Cas systems for kidney diseases.
  1. Autophagy. 2025 Jan 21.
    Induction of lysosome biogenesis is a novel function of the CGAS-STING1 pathway.
    Yinfeng Xu, Wei Wan.
      Induction of macroautophagy/autophagy has been established as an important function elicited by the CGAS-STING1 pathway during pathogen infection. However, it remains unknown whether lysosomal activity within the cell in these settings is concurrently enhanced to cope with the increased autophagic flux. Recently, we discovered that the CGAS-STING1 pathway elevates the degradative capacity of the cell by activating lysosome biogenesis. Intriguingly, we found that STING1-induced GABARAP lipidation, rather than TBK1 activation, serves as the key mediator triggering the nuclear translocation of transcription factor TFEB and enhances the expression of lysosome-related genes. Mechanistically, we demonstrated that lipidated GABARAP on single membranes, regulated by the V-ATPase-ATG16L1 axis, sequesters the FLCN-FNIP complex to abolish its function toward RRAGC-RRAGD, leading to a specific impairment of MTORC1-dependent phosphorylation of TFEB and resulting in its subsequent nuclear translocation. Functionally, we showed that STING1-induced lysosome biogenesis is essential for the clearance of cytoplasmic DNA and the elimination of invading pathogens. Collectively, our findings underscore the induction of lysosome biogenesis as a novel function of the CGAS-STING1 pathway.China; Yinfeng Xu; Email: yinfengxu@hnfnu.edu.cn; Hunan First Normal University, 1015 Feng-Lin-San Road, Changsha, Hunan 410,205, China.
    Keywords:  Autophagy; CGAS; GABARAP; STING1; TFEB; lysosome
    DOI:  https://doi.org/10.1080/15548627.2025.2456064
  2. Redox Biol. 2025 Jan 16. pii: S2213-2317(25)00013-8. [Epub ahead of print]80 103500
    Caloric restriction exacerbates renal post-ischemic injury and fibrosis by modulating mTORC1 signaling and autophagy.
    Lang Shi, Hongchu Zha, Juan Zhao, Haiqian An, Hua Huang, Yao Xia, Ziyu Yan, Zhixia Song, Jiefu Zhu.
       OBJECTIVE: This study investigates the effects of caloric restriction (CR) on renal injury and fibrosis following ischemia-reperfusion injury (IRI), with a focus on the roles of the mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signaling and autophagy.
    METHODS: A mouse model of unilateral IRI with or without CR was used. Renal function was assessed through serum creatinine and blood urea nitrogen levels, while histological analysis and molecular assays evaluated tubular injury, fibrosis, mTORC1 signaling, and autophagy activation. Inducible renal tubule-specific Atg7 knockout mice and autophagy inhibitor 3-MA were used to elucidate autophagy's role in renal outcomes.
    RESULTS: CR exacerbated renal dysfunction, tubular injury, and fibrosis in IRI mice, associated with suppressed mTORC1 signaling and enhanced autophagy. Rapamycin, an mTORC1 inhibitor, mimicked the effects of CR, further supporting the involvement of mTORC1-autophagy pathway. Tubule-specific Atg7 knockout and autophagy inhibitor 3-MA mitigated these effects, indicating a central role for autophagy in CR-induced renal damage. Glucose supplementation, but not branched-chain amino acids (BCAAs), alleviated CR-induced renal fibrosis and dysfunction by restoring mTORC1 activation. Finally, we identified leucyl-tRNA synthetase 1 (LARS1) as a key mediator of nutrient sensing and mTORC1 activation, demonstrating its glucose dependency under CR conditions.
    CONCLUSION: Our study provides novel insights into the interplay between nutrient metabolism, mTORC1 signaling, and autophagy in IRI-induced renal damages, offering potential therapeutic targets for mitigating CR-associated complications after renal IRI.
    Keywords:  Acute kidney injury; Autophagy; Caloric restriction; Ischemia-reperfusion injury; mTORC1
    DOI:  https://doi.org/10.1016/j.redox.2025.103500
  3. Trends Cell Biol. 2025 Jan 21. pii: S0962-8924(25)00001-7. [Epub ahead of print]
    Splice age: mTORC1-mediated RNA splicing in metabolism and ageing.
    Pablo Lanuza-Gracia, Jonas Juan-Mateu, Juan Valcárcel.
      The target of rapamycin complex mTORC1 has key roles in cell growth and metabolism and its inhibition delays ageing. Recent work by Ogawa et al. in Caenorhabditis elegans argues that modulation of pre-mRNA splicing factors and alternative splicing are key mediators of mTORC1 signalling and can enhance longevity.
    DOI:  https://doi.org/10.1016/j.tcb.2025.01.001
  4. Dev Cell. 2025 Jan 10. pii: S1534-5807(24)00778-0. [Epub ahead of print]
    mTor limits autophagy to facilitate cell volume expansion and rapid wound repair in Drosophila embryos.
    Gordana Scepanovic, Negar Balaghi, Katheryn E Rothenberg, Rodrigo Fernandez-Gonzalez.
      Embryonic wounds repair rapidly, with no inflammation or scarring. Embryonic wound healing is driven by collective cell movements facilitated by the increase in the volume of the cells adjacent to the wound. The mechanistic target of rapamycin (mTor) complex 1 (TORC1) is associated with cell growth. We found that disrupting TORC1 signaling in Drosophila embryos prevented cell volume increases and slowed down wound repair. Catabolic processes, such as autophagy, can inhibit cell growth. Five-dimensional microscopy demonstrated that the number of autophagosomes decreased during wound repair, suggesting that autophagy must be tightly regulated for rapid wound healing. mTor inhibition increased autophagy, and activating autophagy prevented cell volume expansion and slowed down wound closure. Finally, reducing autophagy in embryos with disrupted TORC1 signaling rescued cell volume changes and rapid wound repair. Together, our results show that TORC1 activation upon wounding negatively regulates autophagy, allowing cells to increase their volumes to facilitate rapid wound healing.
    Keywords:  Drosophila embryo; cell volume; collective cell movement; epithelial morphogenesis; image analysis; quantitative microscopy; wound healing
    DOI:  https://doi.org/10.1016/j.devcel.2024.12.039
  5. Nat Struct Mol Biol. 2025 Jan 17.
    Cryo-EM reveals cholesterol binding in the lysosomal GPCR-like protein LYCHOS.
    Jie Zhao, Qingya Shen, Xihao Yong, Xin Li, Xiaowen Tian, Suyue Sun, Zheng Xu, Xiaoyu Zhang, Lu Zhang, Hao Yang, Zhenhua Shao, Haoxing Xu, Yiyang Jiang, Yan Zhang, Wei Yan.
      Cholesterol plays a pivotal role in modulating the activity of mechanistic target of rapamycin complex 1 (mTOR1), thereby regulating cell growth and metabolic homeostasis. LYCHOS, a lysosome-localized G-protein-coupled receptor-like protein, emerges as a cholesterol sensor and is capable of transducing the cholesterol signal to affect the mTORC1 function. However, the precise mechanism by which LYCHOS recognizes cholesterol remains unknown. Here, using cryo-electron microscopy, we determined the three-dimensional structural architecture of LYCHOS in complex with cholesterol molecules, revealing a unique arrangement of two sequential structural domains. Through a comprehensive analysis of this structure, we elucidated the specific structural features of these two domains and their collaborative role in the process of cholesterol recognition by LYCHOS.
    DOI:  https://doi.org/10.1038/s41594-024-01470-9
  6. Nat Commun. 2025 Jan 21. 16(1): 896
    N-Cadherin promotes cardiac regeneration by potentiating pro-mitotic β-Catenin signaling in cardiomyocytes.
    Yi-Wei Tsai, Yi-Shuan Tseng, Yu-Shuo Wu, Wei-Lun Song, Min-Yi You, Yun-Chia Hsu, Wen-Pin Chen, Wei-Han Huang, Jia-Ci Chng, Chai-Ling Lim, Ke-Hsuan Wei, Shih-Lei Ben Lai, Wen-Chih Lee, Kai-Chien Yang.
      Adult human hearts exhibit limited regenerative capacity. Post-injury cardiomyocyte (CM) loss can lead to myocardial dysfunction and failure. Although neonatal mammalian hearts can regenerate, the underlying molecular mechanisms remain elusive. Herein, comparative transcriptome analyses identify adherens junction protein N-Cadherin as a crucial regulator of CM proliferation/renewal. Its expression correlates positively with mitotic genes and shows an age-dependent reduction. N-Cadherin is upregulated in the neonatal mouse heart following injury, coinciding with increased CM mitotic activities. N-Cadherin knockdown reduces, whereas overexpression increases, the proliferation activity of neonatal mouse CMs and human induced pluripotent stem cell-derived CMs. Mechanistically, N-Cadherin binds and stabilizes pro-mitotic transcription regulator β-Catenin, driving CM self-renewal. Targeted N-Cadherin deletion in CMs impedes cardiac regeneration in neonatal mice, leading to excessive scarring. N-Cadherin overexpression, by contrast, promotes regeneration in adult mouse hearts following ischemic injury. N-Cadherin targeting presents a promising avenue for promoting cardiac regeneration and restoring function in injured adult human hearts.
    DOI:  https://doi.org/10.1038/s41467-025-56216-y
  7. FASEB J. 2025 Jan 31. 39(2): e70277
    mTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.
    Jingwen Li, Agnete B Madsen, Jonas R Knudsen, Carlos Henriquez-Olguin, Kaspar W Persson, Zhencheng Li, Steffen H Raun, Tianjiao Li, Bente Kiens, Jørgen F P Wojtaszewski, Erik A Richter, Leonardo Nogara, Bert Blaauw, Riki Ogasawara, Thomas E Jensen.
      The kinases AMPK, and mTOR as part of either mTORC1 or mTORC2, are major orchestrators of cellular growth and metabolism. Phosphorylation of mTOR Ser1261 is reportedly stimulated by both insulin and AMPK activation and a regulator of both mTORC1 and mTORC2 activity. Intrigued by the possibilities that Ser1261 might be a convergence point between insulin and AMPK signaling in skeletal muscle, we investigated the regulation and function of this site using a combination of human exercise, transgenic mouse, and cell culture models. Ser1261 phosphorylation on mTOR did not respond to insulin in any of our tested models, but instead responded acutely to contractile activity in human and mouse muscle in an AMPK activity-dependent manner. Contraction-stimulated mTOR Ser1261 phosphorylation in mice was decreased by Raptor muscle knockout (mKO) and increased by Raptor muscle overexpression, yet was not affected by Rictor mKO, suggesting most of Ser1261 phosphorylation occurs within mTORC1 in skeletal muscle. In accordance, HEK293 cells mTOR Ser1261Ala mutation strongly impaired phosphorylation of mTORC1 substrates but not mTORC2 substrates. However, neither mTORC1 nor mTORC2-dependent phosphorylations were affected in muscle-specific kinase-dead AMPK mice with no detectable mTOR Ser1261 phosphorylation in skeletal muscle. Thus, mTOR Ser1261 is an exercise but not insulin-responsive AMPK-dependent phosphosite in human and murine skeletal muscle, playing an unclear role in mTORC1 regulation but clearly not required for mTORC2 activity.
    Keywords:  AMPK; exercise; mTORC1; mTORC2; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202402064R
  8. Cardiovasc Diabetol. 2025 Jan 18. 24(1): 25
    Advances in cardiac organoid research: implications for cardiovascular disease treatment.
    Ziteng Huang, Keran Jia, Yadan Tan, Yang Yu, Wudian Xiao, Xiangyu Zhou, Jingyan Yi, Chunxiang Zhang.
      Globally, cardiovascular diseases remain among the leading causes of mortality, highlighting the urgent need for innovative research models. Consequently, the development of accurate models that simulate cardiac function holds significant scientific and clinical value for both disease research and therapeutic interventions. Cardiac organoids, which are three-dimensional structures derived from the induced differentiation of stem cells, are particularly promising. These organoids not only replicate the autonomous beating and essential electrophysiological properties of the heart but are also widely employed in studies related to cardiac diseases, drug efficacy testing, and regenerative medicine. This review comprehensively surveys the various fabrication techniques used to create cardiac organoids and their diverse applications in modeling a range of cardiac diseases. We emphasize the role of advanced technologies in enhancing the maturation and functionality of cardiac cells, ensuring that these models closely resemble native cardiac tissue. Furthermore, we discuss monitoring techniques and evaluation parameters critical for assessing the performance of cardiac organoids, considering the complex interactions within multi-organ systems. This approach is vital for enhancing precision and efficiency in drug development, allowing for more effective therapeutic strategies. Ultimately, this review aims to provide a thorough and innovative perspective on both fundamental research and clinical treatment of cardiovascular diseases, offering insights that could pave the way for future advancements in understanding and addressing these prevalent health challenges.
    Keywords:  Cardiac diseases; Cardiac organoids; Monitoring techniques; Multi-organ systems
    DOI:  https://doi.org/10.1186/s12933-025-02598-8
  9. Biochim Biophys Acta Mol Cell Res. 2025 Jan 19. pii: S0167-4889(25)00011-4. [Epub ahead of print]1872(3): 119906
    Mitochondrial quality control: Biochemical mechanism of cardiovascular disease.
    Francesca Inferrera, Ylenia Marino, Tiziana Genovese, Salvatore Cuzzocrea, Roberta Fusco, Rosanna Di Paola.
      Mitochondria play a key role in the regulation of energy homeostasis and ATP production in cardiac cells. Mitochondrial dysfunction can trigger several pathological events that contribute to the development and progression of cardiovascular diseases. These mechanisms include the induction of oxidative stress, dysregulation of intracellular calcium cycling, activation of the apoptotic pathway, and alteration of lipid metabolism. This review focuses on the role of mitochondria in intracellular signaling associated with cardiovascular diseases, emphasizing the contributions of reactive oxygen species production and mitochondrial dynamics. Indeed, mitochondrial dysfunction has been implicated in every aspect of cardiovascular disease and is currently being evaluated as a potential target for therapeutic interventions. To treat cardiovascular diseases and improve overall heart health, it is important to better understand these biochemical systems. These findings allow the achievement of targeted therapies and preventive measures. Therefore, this review investigates different studies that demonstrate how changes in mitochondrial dynamics like fusion, fission, and mitophagy contribute to the development or worsening of disorders related to heart diseases by summarizing current research on their role.
    Keywords:  Cardiovascular diseases; Intracellular signaling; Mitochondrial dysfunction; Oxidative stress; Therapeutic interventions
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119906
  10. Kidney Int. 2025 Feb;pii: S0085-2538(24)00481-2. [Epub ahead of print]107(2): 234-254
    KDIGO 2025 clinical practice guideline for the evaluation, management, and treatment of autosomal dominant polycystic kidney disease (ADPKD): executive summary.
    Vicente E Torres, Curie Ahn, Thijs R M Barten, Godela Brosnahan, Melissa A Cadnapaphornchai, Arlene B Chapman, Emilie Cornec-Le Gall, Joost P H Drenth, Ron T Gansevoort, Peter C Harris, Tess Harris, Shigeo Horie, Max C Liebau, Michele Liew, Andrew J Mallett, Changlin Mei, Djalila Mekahli, Dwight Odland, Albert C M Ong, Luiz F Onuchic, York P-C Pei, Ronald D Perrone, Gopala K Rangan, Brian Rayner, Roser Torra, Ethan M Balk, Craig E Gordon, Amy Earley, Reem A Mustafa, Olivier Devuyst.
      The Kidney Disease: Improving Global Outcomes (KDIGO) 2025 Clinical Practice Guideline for the Evaluation, Management, and Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) represents the first KDIGO guideline on this subject. Its scope includes nomenclature, diagnosis, prognosis, and prevalence; kidney manifestations; chronic kidney disease (CKD) management and progression, kidney failure, and kidney replacement therapy; therapies to delay progression of kidney disease; polycystic liver disease; intracranial aneurysms and other extrarenal manifestations; lifestyle and psychosocial aspects; pregnancy and reproductive issues; pediatric issues; and approaches to the management of people with ADPKD. The guideline has been developed with patient partners, clinicians, and researchers around the world, with the goal to generate a useful resource for healthcare providers and patients by providing actionable recommendations. The development of this guideline followed an explicit process of evidence review and appraisal, based on a rigorous, formal systematic literature review. The strength of recommendations follows the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The guideline also provides practice points serving to direct clinical care or activities relating to areas for which a systematic review was not conducted. Limitations of the evidence are discussed. Research recommendations to address gaps in knowledge, and implications for policy and payment, are provided. The guideline targets a broad audience of healthcare providers, people living with ADPKD, and stakeholders involved in the various aspects of ADPKD care.
    Keywords:  ADPKD; evidence-based; guideline; monogenic disease; nomenclature
    DOI:  https://doi.org/10.1016/j.kint.2024.07.010
  11. Prog Mol Biol Transl Sci. 2025 ;pii: S1877-1173(24)00169-8. [Epub ahead of print]210 149-162
    Advances in CRISPR-Cas systems for kidney diseases.
    Bhupendra Puri, Yogesh A Kulkarni, Anil Bhanudas Gaikwad.
      Recent advances in CRISPR-Cas systems have revolutionised the study and treatment of kidney diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), diabetic kidney disease (DKD), lupus nephritis (LN), and polycystic kidney disease (PKD). CRISPR-Cas technology offers precise and versatile tools for genetic modification in monogenic kidney disorders such as PKD and Alport syndrome. Recent advances in CRISPR technology have also shown promise in addressing other kidney diseases like AKI, CKD, and DKD. CRISPR-Cas holds promise to edit genetic mutations underlying these conditions, potentially leading to more effective and long-lasting treatments. Furthermore, the adaptability of CRISPR-Cas systems allows for developing tailored therapeutic strategies that specifically target the genetic and molecular mechanisms contributing to different kidney diseases. Beyond DNA modifications, CRISPR-Cas technologies also enable editing noncoding RNA, such as lncRNAs and miRNAs, in kidney diseases. Despite these advancements, significant challenges persist, including delivery efficiency to specific kidney cells and potential off-target effects. However, the rapid progress in CRISPR-Cas technology suggests a transformative impact on the future management of kidney diseases, offering the potential for enhanced patient outcomes through personalised and precise therapeutic approaches. This chapter highlights the recent advancement of CRISPR-Cas systems and their potential applications in various kidney diseases.
    Keywords:  Acute kidney injury; CRISPR-Cas system; Chronic kidney disease; Diabetic kidney disease; Kidney diseases; Lupus nephritis; Polycystic kidney disease
    DOI:  https://doi.org/10.1016/bs.pmbts.2024.07.020
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