PXD023021

PXD023021 is an original dataset announced via ProteomeXchange.

Title	Ribosomal protein deficiency generates proteotoxic stress that is alleviated by TOR inhibition
Description	Ribosomes are multi-component molecular machines that synthesize all the proteins of living cells. Understandably, most genes encoding the protein components of ribosomes are essential. Reduction in gene dosage is often viable but deleterious and associated with human syndromes, collectively known as ribosomopathies. The cell biological basis of these pathologies has remained unclear. Here, we model human ribosomopathies in Drosophila and find widespread apoptosis and cellular stress in the resulting animals. This is not caused by insufficient protein synthesis, as reasonably expected. Instead, ribosomal protein deficiency elicits proteotoxic stress, which, we suggest, is caused by the accumulation of misfolded proteins that overwhelm the protein degradation machinery. We find that dampening the integrated stress response or autophagy worsens the harm inflicted by ribosomal protein deficiency, suggesting that these activities could be cytoprotective. Inhibition of TOR activity, which dampens ribosomal protein production, slows down protein synthesis and stimulates autophagy, reduces proteotoxic stress in our ribosomopathy model. Interventions that stimulate autophagy, combined with means of boosting protein quality control, could form the basis of a therapeutic strategy for this class of diseases.
HostingRepository	PRIDE
AnnounceDate	2021-01-14
AnnouncementXML	Submission_2021-01-14_04:26:13.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joanna Kirkpatrick
SpeciesList	scientific name: Drosophila melanogaster (Fruit fly); NCBI TaxID: 7227;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-12-09 08:28:25	ID requested
⏵ 1	2021-01-14 04:26:13	announced

Dataset with its publication pending

submitter keyword: ribosomes, protein translation, ribosomopathies, proteotoxic stress, autophagy, protein aggregates, apoptosis, p62, eIF2, TOR, RPS23, RPS26, Diamond Blackfan anemia

Jean-Paul Vincent
contact affiliation	The Francis Crick Institute, London NW1 1AT, UK
contact email	jp.vincent@crick.ac.uk
lab head
Joanna Kirkpatrick
contact affiliation	The Francis Crick Institute
contact email	joanna.kirkpatrick@crick.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD023021
     1. Label: PRIDE project
     2. Name: Ribosomal protein deficiency generates proteotoxic stress that is alleviated by TOR inhibition