bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2024–08–25
eight papers selected by
Irene Sambri, TIGEM
  1. Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway.
  2. Nutrient Sensing of mTORC1 signaling in cancer and aging.
  3. The Estrogen Receptor-Related Orphan Receptors (ERRs) Regulate Autophagy through TFEB.
  4. The SGLT2 inhibitor dapagliflozin ameliorates renal fibrosis in hyperuricemic nephropathy.
  5. Targeting Autophagy: A Promising Therapeutic Strategy for Diabetes Mellitus and Diabetic Nephropathy.
  6. SGLT2 inhibitors: how do they affect the cardiac cells.
  7. An old dog with new tricks: TFEB promotes syncytin expression and cell fusion in the human placenta.
  8. TFEB controls expression of human syncytins during cell-cell fusion.
  1. Proc Natl Acad Sci U S A. 2024 Aug 27. 121(35): e2322755121
    Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway.
    Max L Valenstein, Pranav V Lalgudi, Xin Gu, Jibril F Kedir, Martin S Taylor, Raghu R Chivukula, David M Sabatini.
      The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth and metabolism in response to many environmental cues, including nutrients. Amino acids signal to mTORC1 by modulating the guanine nucleotide loading states of the heterodimeric Rag GTPases, which bind and recruit mTORC1 to the lysosomal surface, its site of activation. The Rag GTPases are tethered to the lysosome by the Ragulator complex and regulated by the GATOR1, GATOR2, and KICSTOR multiprotein complexes that localize to the lysosomal surface through an unknown mechanism(s). Here, we show that mTORC1 is completely insensitive to amino acids in cells lacking the Rag GTPases or the Ragulator component p18. Moreover, not only are the Rag GTPases and Ragulator required for amino acids to regulate mTORC1, they are also essential for the lysosomal recruitment of the GATOR1, GATOR2, and KICSTOR complexes, which stably associate and traffic to the lysosome as the "GATOR" supercomplex. The nucleotide state of RagA/B controls the lysosomal association of GATOR, in a fashion competitively antagonized by the N terminus of the amino acid transporter SLC38A9. Targeting of Ragulator to the surface of mitochondria is sufficient to relocalize the Rags and GATOR to this organelle, but not to enable the nutrient-regulated recruitment of mTORC1 to mitochondria. Thus, our results reveal that the Rag-Ragulator complex is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway and underscore that mTORC1 activation requires signal transduction on the lysosomal surface.
    Keywords:  biochemistry; mTOR signaling; nutrient sensing
    DOI:  https://doi.org/10.1073/pnas.2322755121
  2. Semin Cancer Biol. 2024 Aug 14. pii: S1044-579X(24)00059-2. [Epub ahead of print]
    Nutrient Sensing of mTORC1 signaling in cancer and aging.
    Cong Jiang, Xiao Tan, Ning Liu, Peiqiang Yan, Tao Hou, Wenyi Wei.
      The mechanistic target of rapamycin complex 1 (mTORC1) is indispensable for preserving cellular and organismal homeostasis by balancing the anabolic and catabolic processes in response to various environmental cues, such as nutrients, growth factors, energy status, oxygen levels, and stress. Dysregulation of mTORC1 signaling is associated with the progression of many types of human disorders including cancer, age-related diseases, neurodegenerative disorders, and metabolic diseases. The way mTORC1 senses various upstream signals and converts them into specific downstream responses remains a crucial question with significant impacts for our perception of the related physiological and pathological process. In this review, we discuss the recent molecular and functional insights into the nutrient sensing of the mTORC1 signaling pathway, along with the emerging role of deregulating nutrient-mTORC1 signaling in cancer and age-related disorders.
    Keywords:  amino acid; kinase; mTOR; mTORC1; mTORC2; nutrient sensing; phosphorylation; tumorigenesis
    DOI:  https://doi.org/10.1016/j.semcancer.2024.08.001
  3. Mol Pharmacol. 2024 Aug 21. pii: MOLPHARM-AR-2024-000889. [Epub ahead of print]
    The Estrogen Receptor-Related Orphan Receptors (ERRs) Regulate Autophagy through TFEB.
    McKenna Losby, Matthew Hayes, Aurore Valfort, Danesh H Sopariwala, Ryan Sanders, John K Walker, Weiyi Xu, Vihang A Narkar, Lilei Zhang, Cyrielle Billon, Thomas P Burris.
      Autophagy is an essential self-degradative and recycling mechanism that maintains cellular homeostasis. Estrogen receptor-related orphan receptors (ERRs) are fundamental in regulating cardiac metabolism and function. Previously, we showed that ERR agonists improve cardiac function in models of heart failure and induce autophagy in cardiomyocytes. Here, we characterized a mechanism by which ERRs induce the autophagy pathway in cardiomyocytes. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway and has been shown to be important in cardiac autophagy. We discovered that TFEB is a direct ERR target gene whose expression is induced by ERR agonists. Activation of ERR results in increased TFEB expression in both neonatal rat ventricular myocytes and C2C12 myoblast cells. ERR-dependent increases in TFEB expression result in increased expression of an array of TFEB target genes, which are critical for the stimulation of autophagy. Pharmacologically targeting ERR is a promising potential method for the treatment of many diseases where stimulation of autophagy may be therapeutic, including heart failure. Significance Statement Estrogen receptor-related receptor agonists function as exercise mimetics and also display efficacy in animal models of metabolic disease, obesity, and heart failure.
    Keywords:  drug discovery; heart/cardiac; nuclear receptors; steroids
    DOI:  https://doi.org/10.1124/molpharm.124.000889
  4. Cell Rep Med. 2024 Aug 20. pii: S2666-3791(24)00411-7. [Epub ahead of print]5(8): 101690
    The SGLT2 inhibitor dapagliflozin ameliorates renal fibrosis in hyperuricemic nephropathy.
    Hongtu Hu, Weiwei Li, Yiqun Hao, Zhuan Peng, Zhengping Zou, Jiali Wei, Ying Zhou, Wei Liang, Yun Cao.
      Hyperuricemic nephropathy (HN) is a global metabolic disorder characterized by uric acid (UA) metabolism dysfunction, resulting in hyperuricemia (HUA) and tubulointerstitial fibrosis (TIF). Sodium-dependent glucose transporter 2 inhibitor, dapagliflozin, has shown potential in reducing serum UA levels in patients with chronic kidney disease (CKD), though its protective effects against HN remain uncertain. This study investigates the functional, pathological, and molecular changes in HN through histological, biochemical, and transcriptomic analyses in patients, HN mice, and UA-stimulated HK-2 cells. Findings indicate UA-induced tubular dysfunction and fibrotic activation, which dapagliflozin significantly mitigates. Transcriptomic analysis identifies estrogen-related receptor α (ERRα), a downregulated transcription factor in HN. ERRα knockin mice and ERRα-overexpressed HK-2 cells demonstrate UA resistance, while ERRα inhibition exacerbates UA effects. Dapagliflozin targets ERRα, activating the ERRα-organic anion transporter 1 (OAT1) axis to enhance UA excretion and reduce TIF. Furthermore, dapagliflozin ameliorates renal fibrosis in non-HN CKD models, underscoring the therapeutic significance of the ERRα-OAT1 axis in HN and CKD.
    Keywords:  ERRα; OAT1; dapagliflozin; hyperuricemic nephropathy; tubulointerstitial fibrosis
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101690
  5. Diabetes Ther. 2024 Aug 21.
    Targeting Autophagy: A Promising Therapeutic Strategy for Diabetes Mellitus and Diabetic Nephropathy.
    Qi-Rui Li, Hui-Ying Xu, Rui-Ting Ma, Yuan-Yuan Ma, Mei-Juan Chen.
      Diabetes mellitus (DM) significantly impairs patients' quality of life, primarily because of its complications, which are the leading cause of mortality among individuals with the disease. Autophagy has emerged as a key process closely associated with DM, including its complications such as diabetic nephropathy (DN). DN is a major complication of DM, contributing significantly to chronic kidney disease and renal failure. The intricate connection between autophagy and DM, including DN, highlights the potential for new therapeutic targets. This review examines the interplay between autophagy and these conditions, aiming to uncover novel approaches to treatment and enhance our understanding of their underlying pathophysiology. It also explores the role of autophagy in maintaining renal homeostasis and its involvement in the development and progression of DM and DN. Furthermore, the review discusses natural compounds that may alleviate these conditions by modulating autophagy.
    Keywords:  Autophagy; Diabetes mellitus; Diabetic nephropathy; Natural substances
    DOI:  https://doi.org/10.1007/s13300-024-01641-3
  6. Mol Cell Biochem. 2024 Aug 19.
    SGLT2 inhibitors: how do they affect the cardiac cells.
    Betul Rabia Erdogan, Ebru Arioglu-Inan.
      The first sodium-glucose cotransporter-2 inhibitor (SGLT2I), canagliflozin, was approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in 2013. Since then, other members of this drug class (such as dapagliflozin, empagliflozin, and ertugliflozin) have become widely used. Unlike classical antidiabetic agents, these drugs do not interfere with insulin secretion or action, but instead promote renal glucose excretion. Since their approval, many preclinical and clinical studies have been conducted to investigate the diverse effects of SGLT2Is. While originally introduced as antidiabetic agents, the SGLT2Is are now recognized as pillars in the treatment of heart failure and chronic kidney disease, in patients with or without diabetes. The beneficial cardiac effects of this class have been attributed to several mechanisms. Among these, SGLT2Is inhibit fibrosis, hypertrophy, apoptosis, inflammation, and oxidative stress. They regulate mitochondrial function and ion transport, and stimulate autophagy through several underlying mechanisms. This review details the potential effects of SGLT2Is on cardiac cells.
    Keywords:  Apoptosis; Cardiac cells; Fibrosis; Inflammation; Ion transport; SGLT2 inhibitors
    DOI:  https://doi.org/10.1007/s11010-024-05084-z
  7. Genes Dev. 2024 Aug 22.
    An old dog with new tricks: TFEB promotes syncytin expression and cell fusion in the human placenta.
    Stephen J Renaud.
      In the human placenta, cell fusion is crucial for forming the syncytiotrophoblast, a multinucleated giant cell essential for maintaining pregnancy and ensuring fetal health. The formation of the syncytiotrophoblast is catalyzed by the evolutionarily modern fusogens syncytin-1 and syncytin-2. In this issue of Genes & Development, Esbin and colleagues (doi:10.1101/gad.351633.124) reveal a critical role for the transcription factor TFEB in the regulation of syncytin expression and the promotion of trophoblast fusion. Notably, TFEB's pro-fusion role operates independently of its well-known functions in lysosome biogenesis and autophagy, suggesting that TFEB has acquired additional functions to promote cell fusion in the human placenta.
    Keywords:  TFEB; cell fusion; placenta; single molecule imaging; syncytin; transcription factor
    DOI:  https://doi.org/10.1101/gad.352198.124
  8. Genes Dev. 2024 Aug 21.
    TFEB controls expression of human syncytins during cell-cell fusion.
    Meagan N Esbin, Liza Dahal, Vinson B Fan, Joey McKenna, Eric Yin, Xavier Darzacq, Robert Tjian.
      During human development, a temporary organ is formed, the placenta, which invades the uterine wall to support nutrient, oxygen, and waste exchange between the mother and fetus until birth. Most of the human placenta is formed by a syncytial villous structure lined by syncytialized trophoblasts, a specialized cell type that forms via cell-cell fusion of underlying progenitor cells. Genetic and functional studies have characterized the membrane protein fusogens Syncytin-1 and Syncytin-2, both of which are necessary and sufficient for human trophoblast cell-cell fusion. However, identification and characterization of upstream transcriptional regulators regulating their expression have been limited. Here, using CRISPR knockout in an in vitro cellular model of syncytiotrophoblast development (BeWo cells), we found that the transcription factor TFEB, mainly known as a regulator of autophagy and lysosomal biogenesis, is required for cell-cell fusion of syncytiotrophoblasts. TFEB translocates to the nucleus, exhibits increased chromatin interactions, and directly binds the Syncytin-1 and Syncytin-2 promoters to control their expression during differentiation. Although TFEB appears to play a critical role in syncytiotrophoblast differentiation, ablation of TFEB largely does not affect lysosomal gene expression or lysosomal biogenesis in differentiating BeWo cells, suggesting a previously uncharacterized role for TFEB in controlling the expression of human syncytins.
    Keywords:  TFEB; cell fusion; placenta; single-molecule imaging; syncytin; transcription factor
    DOI:  https://doi.org/10.1101/gad.351633.124
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