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Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates ageing in mice

ABSTRACT: Nucleolar stress (NS) kills cells by p53-dependent and independent manners. To investigate the mechanisms of p53-indendendent toxicity, we here used (PR)n arginine-rich peptides as inducers of NS, which are found in patients of some neurodegenerative diseases. Although these peptides generate NS, how this translates to toxicity is poorly understood. We here reveal that whereas (PR)n expression leads to an overall decrease in protein abundance for the majority of the proteome, this occurs concomitant to an accumulation of free ribosomal proteins in the cytoplasm, which is a hallmark of ribosomopathies. Conversely, cells with acquired resistance to (PR)n peptides present a global downregulation of ribosomal proteins and low levels of mTOR signaling. In mice, systemic expression of (PR)97 drives widespread NS and accelerated ageing, associated to an increased expression of ribosomal proteins and mTOR hyperactivation. Furthermore, the progeroid phenotype of (PR)97-expressing mice is alleviated by rapamycin. Importantly, we show that the generalized accumulation of free ribosomal proteins is not restricted to (PR)n peptides, but is a common outcome in response to chemical or genetic perturbations that generate NS such as Actinomycin D, TIF-IA depletion or the expression or mutant HMGB1 forms recently associated to rare human diseases. Together, our study provides in vivo evidence for the role of NS as a driver of ageing in mammals, and describes a general model to understand the mechanisms behind p53-independent cell toxicity caused by NS.

INSTRUMENT(S): Q Exactive Plus, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Pilar Ximenez-Embun

LAB HEAD: Marta Isasa

PROVIDER: PXD043752 | Pride | 2024-03-11

REPOSITORIES: Pride

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Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates ageing in mice

Project description:Nucleolar stress (NS) kills cells by p53-dependent and independent manners. To investigate the mechanisms of p53-indendendent toxicity, we here used (PR)n arginine-rich peptides as inducers of NS, which are found in patients of some neurodegenerative diseases. Although these peptides generate NS, how this translates to toxicity is poorly understood. We here reveal that whereas (PR)n expression leads to an overall decrease in protein abundance for the majority of the proteome, this occurs concomitant to an accumulation of free ribosomal proteins in the cytoplasm, which is a hallmark of ribosomopathies. Conversely, cells with acquired resistance to (PR)n peptides present a global downregulation of ribosomal proteins and low levels of mTOR signaling. In mice, systemic expression of (PR)97 drives widespread NS and accelerated ageing, associated to an increased expression of ribosomal proteins and mTOR hyperactivation. Furthermore, the progeroid phenotype of (PR)97-expressing mice is alleviated by rapamycin. Importantly, we show that the generalized accumulation of free ribosomal proteins is not restricted to (PR)n peptides, but is a common outcome in response to chemical or genetic perturbations that generate NS such as Actinomycin D, TIF-IA depletion or the expression or mutant HMGB1 forms recently associated to rare human diseases. Together, our study provides in vivo evidence for the role of NS as a driver of ageing in mammals, and describes a general model to understand the mechanisms behind p53-independent cell toxicity caused by NS.

2024-03-08 | PXD046380 | Pride

Analysis of mRNA expression of livers from (PR)97 expressing mice

2024-03-08 | GSE239319 | GEO

Impact of oligoarginine peptides in ribosome composition and chromatin proteomes

Project description:Expanded intronic GGGGCC repeats in C9ORF72 produce several dipeptides, from which the two that contain arginine, (PR)n and (GR)n, accumulate at nucleoli and kill cells. While this toxicity plays an important role in ALS pathogenesis, its mechanism remains unknown. We here show that PR dipeptides bind avidly to DNA and RNA, so that any cellular reaction involving nucleic acids is impaired by the dipeptides. Consistently, PR-induced cell death can be rescued by addition of non-coding oligonucleotides. Interestingly, the effects of PR dipeptides are to a large extent mimicked by protamine, a sperm-specific Arg-rich protein, and the toxicity of either protamine or PR dipeptides is rescued by the anticoagulant heparin. We propose that the generalized coating of nucleic acids by Arg-rich peptides accounts for the toxicity of C9ORF72 mutations in ALS.

2021-04-12 | PXD010555 | Pride

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Project description:Oral tongue cancer: p53 NS+ vs. p53 NS- tumor

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The gene profile of zebrafish guanine binding protein-like 2 (Gnl2) mutant embryos versus wild-type embryos at 22 hours post-fertilization

Project description:Nucleostemin (NS), a member of a family of nucleolar GTP-binding proteins, is highly expressed in proliferating cells and implicated in the control of cell cycle progression, the maintenance of stem cells, and the regulation of cancer cells. The depletion of NS in cell lines and invertebrate animals has been demonstrated to result in defective ribosome biogenesis, while both depletion and overexpression of NS are able to stabilize the tumor suppressor p53 protein. While the existence of p53-independent functions of NS has been previously suggested, these roles to date remain unclear. Here, we report two zebrafish mutants recovered from forward and reverse genetic screens that encode two members of this nucleolar protein family, Guanine nucleotide binding-protein-like 2 (Gnl2) and Gnl3/Nucleostemin (Ns). We show that Gnl2 and Ns are required for pre-rRNA processing and the production of the 60S ribosomal subunit in the developing zebrafish embryo. In addition, we demonstrate that these proteins are required for correct timing of neural differentiation in the brain and retina. In both mutants, cell cycle regulators such as cyclinD1 and the cell cycle inhibitor cdkn1c/p57kip2 are aberrantly expressed. Concomitantly, retinal progenitors fail to exit the cell cycle in a timely fashion and differentiation of retinal cell types is delayed. We show that loss of either Gnl2 or Ns induces the stabilization of p53 and apoptosis in the brain, however the retinal cell differentiation defect in gnl2 mutants is independent of p53 status. This work demonstrates that the loss of either Gnl2 or Ns results in ribosome biogenesis and neural differentiation defects in vertebrates. In addition, the data suggests that the latter phenotype of gnl2 mutants is due to an increase in expression of cell cycle markers cyclinD1 and p57/kip2 and not to the stabilization of p53.

2010-03-31 | GSE21134 | GEO

Impact of oligoarginine peptides in RNA-binding proteomes

2021-04-12 | PXD014085 | Pride

Esophageal Squamous Cell Carcinoma tumors from Indian patients: nuclear-stabilized p53 (NS+) versus unstable p53 (NS-) protein

Project description:Transcriptional profiling of Esophageal Squamous Cell Carcinoma (ESCC) tumors comparing samples harbouring nuclear-stabilized p53 (NS+) versus unstable p53 (NS-) protein, determined through immunohistochemistry (IHC) staining of the tumor sections. The goal was to identify the genes that were differentially regulated between NS+ and NS- ESCC samples.

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Molecular characterization of Quebec Cohort of Primary Breast Cancer FFPE Tissues on the Human Cancer Panel

Project description:Analysis of 97 formalin-fixed, paraffin-embedded (FFPE) primary breast tumors using Illumina DASL microarray technology on a Custom Breast Cancer Panel and the Illumina Human Cancer Panel. Molecular markers between the pathology defined subtypes of breast cancer were assessed to hypothesize potential therapeutic targets specific to the subtypes Molecular Characterization of 97 primary breast tumor formalin-fixed, paraffin-embedded (FFPE) specimens including 24 triple negative (TN: ER-, PR-, HER2-), 9 HER2-positive (HER2+: ER-, PR-, HER2+), and 64 hormone receptor-positive (HR+: ER+ and/or PR+). 91 of the 97 specimens were characterized on the Illumina Human Cancer DASL Panel and 86 of 97 specimens were characterized on a custom Breast Cancer DASL Panel, 80 of these specimens were common to both the Human Cancer DASL Panel and the custom Breast Cancer DASL Panel.

2009-10-23 | E-GEOD-17650 | biostudies-arrayexpress

Oral tongue cancer: p53 NS+ vs. p53 NS- tumor

Project description:Transcriptional profiling of squamous cell carcinoma of oral tongue, comparing p53 NS+ and p53 NS- tumors. Goal was to determine differentially expressed genes between them based on global gene expression.

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2 hydroxyglutarate prodution in neurospheres from IDH1 mouse glioma model #2

Project description:Evaluation of 2HG and a-ketoglutarate in tumor neurospheres (NS) genertated from the mice brain tumors haboring specific genetic lesions: NRAS overexpression, p53 knockdown plus or minus IDH1 mutated and ATRX knockdown.

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