bims-raghud Biomed News
on RagGTPases in human diseases
Issue of 2024–11–24
six papers selected by
Irene Sambri, TIGEM
  1. Nutrient control of growth and metabolism through mTORC1 regulation of mRNA splicing.
  2. Structure of the human TSC:WIPI3 lysosomal recruitment complex.
  3. Profiling of insulin-resistant kidney models and human biopsies reveals common and cell-type-specific mechanisms underpinning Diabetic Kidney Disease.
  4. Dynamic Kidney Organoid Microphysiological Analysis Platform.
  5. PINK1 controls RTN3L-mediated ER autophagy by regulating peripheral tubule junctions.
  6. The crosstalk of Wnt/β-catenin signaling and p53 in acute kidney injury and chronic kidney disease.
  1. Mol Cell. 2024 Nov 15. pii: S1097-2765(24)00877-3. [Epub ahead of print]
    Nutrient control of growth and metabolism through mTORC1 regulation of mRNA splicing.
    Takafumi Ogawa, Meltem Isik, Ziyun Wu, Kiran Kurmi, Jin Meng, Sungyun Cho, Gina Lee, L Paulette Fernandez-Cardenas, Masaki Mizunuma, John Blenis, Marcia C Haigis, T Keith Blackwell.
      Cellular growth and organismal development are remarkably complex processes that require the nutrient-responsive kinase mechanistic target of rapamycin complex 1 (mTORC1). Anticipating that important mTORC1 functions remained to be identified, we employed genetic and bioinformatic screening in C. elegans to uncover mechanisms of mTORC1 action. Here, we show that during larval growth, nutrients induce an extensive reprogramming of gene expression and alternative mRNA splicing by acting through mTORC1. mTORC1 regulates mRNA splicing and the production of protein-coding mRNA isoforms largely independently of its target p70 S6 kinase (S6K) by increasing the activity of the serine/arginine-rich (SR) protein RSP-6 (SRSF3/7) and other splicing factors. mTORC1-mediated mRNA splicing regulation is critical for growth; mediates nutrient control of mechanisms that include energy, nucleotide, amino acid, and other metabolic pathways; and may be conserved in humans. Although mTORC1 inhibition delays aging, mTORC1-induced mRNA splicing promotes longevity, suggesting that when mTORC1 is inhibited, enhancement of this splicing might provide additional anti-aging benefits.
    Keywords:  C. elegans; SR proteins; development; gene expression; growth; human cell growth; longevity; mRNA splicing; mTORC1; metabolism; nutrient response
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.037
  2. Sci Adv. 2024 Nov 22. 10(47): eadr5807
    Structure of the human TSC:WIPI3 lysosomal recruitment complex.
    Charles Bayly-Jones, Christopher J Lupton, Laura D'Andrea, Yong-Gang Chang, Gareth D Jones, Joel R Steele, Hari Venugopal, Ralf B Schittenhelm, Michelle L Halls, Andrew M Ellisdon.
      Tuberous sclerosis complex (TSC) is targeted to the lysosomal membrane, where it hydrolyzes RAS homolog-mTORC1 binding (RHEB) from its GTP-bound to GDP-bound state, inhibiting mechanistic target of rapamycin complex 1 (mTORC1). Loss-of-function mutations in TSC cause TSC disease, marked by excessive tumor growth. Here, we overcome a high degree of continuous conformational heterogeneity to determine the 2.8-Å cryo-electron microscopy (cryo-EM) structure of the complete human TSC in complex with the lysosomal recruitment factor WD repeat domain phosphoinositide-interacting protein 3 (WIPI3). We discover a previously undetected amino-terminal TSC1 HEAT repeat dimer that clamps onto a single TSC wing and forms a phosphatidylinositol phosphate (PIP)-binding pocket, which specifically binds monophosphorylated PIPs. These structural advances provide a model by which WIPI3 and PIP-signaling networks coordinate to recruit TSC to the lysosomal membrane to inhibit mTORC1. The high-resolution TSC structure reveals previously unrecognized mutational hotspots and uncovers crucial insights into the mechanisms of TSC dysregulation in disease.
    DOI:  https://doi.org/10.1126/sciadv.adr5807
  3. Nat Commun. 2024 Nov 19. 15(1): 10018
    Profiling of insulin-resistant kidney models and human biopsies reveals common and cell-type-specific mechanisms underpinning Diabetic Kidney Disease.
    BEAt-DKD consortium
      Diabetic kidney disease (DKD) is the leading cause of end stage kidney failure worldwide, of which cellular insulin resistance is a major driver. Here, we study key human kidney cell types implicated in DKD (podocytes, glomerular endothelial, mesangial and proximal tubular cells) in insulin sensitive and resistant conditions, and perform simultaneous transcriptomics and proteomics for integrated analysis. Our data is further compared with bulk- and single-cell transcriptomic kidney biopsy data from early- and advanced-stage DKD patient cohorts. We identify several consistent changes (individual genes, proteins, and molecular pathways) occurring across all insulin-resistant kidney cell types, together with cell-line-specific changes occurring in response to insulin resistance, which are replicated in DKD biopsies. This study provides a rich data resource to direct future studies in elucidating underlying kidney signalling pathways and potential therapeutic targets in DKD.
    DOI:  https://doi.org/10.1038/s41467-024-54089-1
  4. bioRxiv. 2024 Oct 29. pii: 2024.10.27.620552. [Epub ahead of print]
    Dynamic Kidney Organoid Microphysiological Analysis Platform.
    SoonGweon Hong, Minsun Song, Tomoya Miyoshi, Ryuji Morizane, Joseph V Bonventre, Luke P Lee.
      Kidney organoids, replicating human development, pathology, and drug responses, are a promising model for advancing bioscience and pharmaceutical innovation. However, reproducibility, accuracy, and quantification challenges hinder their broader utility for advanced biological and pharmaceutical applications. Herein, we present a dynamic kidney organoid microphysiological analysis platform (MAP), designed to enhance organoid modeling and assays within physiologically relevant environments, thereby expanding their utility in advancing kidney physiology and pathology research. First, precise control of the dynamic microenvironment in MAP enhances the ability to fine-tune nephrogenic intricacies, facilitating high-throughput and reproducible human kidney organoid development. Also, MAP's miniaturization of kidney organoids significantly advances pharmaceutical research by allowing for detailed analysis of entire nephron segments, which is crucial for assessing the nephrotoxicity and safety of drugs. Furthermore, the MAP's application in disease modeling faithfully recapitulates pathological development and functions as a valuable testbed for therapeutic exploration in polycystic kidney diseases. We envision the kidney organoid MAP enhancing pharmaceutical research, standardizing processes, and improving analytics, thereby elevating the quality and utility of organoids in biology, pharmacology, precision medicine, and education.
    DOI:  https://doi.org/10.1101/2024.10.27.620552
  5. J Cell Biol. 2024 Dec 02. pii: e202407193. [Epub ahead of print]223(12):
    PINK1 controls RTN3L-mediated ER autophagy by regulating peripheral tubule junctions.
    Ravi Chidambaram, Kamal Kumar, Smriti Parashar, Gowsalya Ramachandran, Shuliang Chen, Susan Ferro-Novick.
      Here, we report that the RTN3L-SEC24C endoplasmic reticulum autophagy (ER-phagy) receptor complex, the CUL3KLHL12 E3 ligase that ubiquitinates RTN3L, and the FIP200 autophagy initiating protein, target mutant proinsulin (Akita) condensates for lysosomal delivery at ER tubule junctions. When delivery was blocked, Akita condensates accumulated in the ER. In exploring the role of tubulation in these events, we unexpectedly found that loss of the Parkinson's disease protein, PINK1, reduced peripheral tubule junctions and blocked ER-phagy. Overexpression of the PINK1 kinase substrate, DRP1, increased junctions, reduced Akita condensate accumulation, and restored lysosomal delivery in PINK1-depleted cells. DRP1 is a dual-functioning protein that promotes ER tubulation and severs mitochondria at ER-mitochondria contact sites. DRP1-dependent ER tubulating activity was sufficient for suppression. Supporting these findings, we observed PINK1 associating with ER tubules. Our findings show that PINK1 shapes the ER to target misfolded proinsulin for RTN3L-SEC24C-mediated macro-ER-phagy at defined ER sites called peripheral junctions. These observations may have important implications for understanding Parkinson's disease.
    DOI:  https://doi.org/10.1083/jcb.202407193
  6. Kidney Res Clin Pract. 2024 Nov 18.
    The crosstalk of Wnt/β-catenin signaling and p53 in acute kidney injury and chronic kidney disease.
    Wen-Hua Ming, Lin Wen, Wen-Juan Hu, Rong-Fang Qiao, Yang Zhou, Bo-Wei Su, Ya-Nan Bao, Ping Gao, Zhi-Lin Luan.
      Wnt/β-catenin is a signaling pathway associated with embryonic development, organ formation, cancer, and fibrosis. Its activation can repair kidney damage during acute kidney injury (AKI) and accelerate the occurrence of renal fibrosis after chronic kidney disease (CKD). Interestingly, p53 has also been found as a key modulator in AKI and CKD in recent years. Meantime, some studies have found crosstalk between Wnt/β-catenin signaling pathways and p53, but more evidence is required on whether they have synergistic effects in renal disease progression. This article reviews the role and therapeutic targets of Wnt/β-catenin and p53 in AKI and CKD and proposes for the first time that Wnt/β-catenin and p53 have a synergistic effect in the treatment of renal injury.
    Keywords:  Acute kidney injury; Chronic renal insufficiency; Crosstalk; Wnt/β-catenin; p53
    DOI:  https://doi.org/10.23876/j.krcp.23.344
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