PXD046380-2

PXD046380 is an original dataset announced via ProteomeXchange.

Title	Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates ageing in mice
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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:32:32.491.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eduardo Zarzuela
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue
Instrument	Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2023-10-25 03:48:35	ID requested
1	2024-03-08 03:09:50	announced
⏵ 2	2024-10-22 06:32:32	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: Nucleolar stress, mTOR., Translation, Ribosomopathy, DPRs

Javier Muñoz
contact affiliation	CNIO
contact email	javier.munozperalta@osakidetza.eus
lab head
Eduardo Zarzuela
contact affiliation	Centro Nacional de Investigaciones Oncológicas
contact email	eduzarfer@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/03/PXD046380

PRIDE project URI

• PRIDE
  1. PXD046380
     1. Label: PRIDE project
     2. Name: Nucleolar stress caused by arginine-rich peptides triggers a ribosomopathy and accelerates ageing in mice