Publication Date
4-1-2024
Journal
Nature Cell Biology
DOI
10.1038/s41556-024-01387-x
PMID
38553595
PMCID
PMC11021199
PubMedCentral® Posted Date
3-29-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Intrinsically Disordered Proteins, Cyclophilin A, RNA-Binding Proteins, Hematopoietic Stem Cells, Chaperones, Ageing, Haematopoietic stem cells
Abstract
Loss of protein function is a driving force of ageing. We have identified peptidyl-prolyl isomerase A (PPIA or cyclophilin A) as a dominant chaperone in haematopoietic stem and progenitor cells. Depletion of PPIA accelerates stem cell ageing. We found that proteins with intrinsically disordered regions (IDRs) are frequent PPIA substrates. IDRs facilitate interactions with other proteins or nucleic acids and can trigger liquid-liquid phase separation. Over 20% of PPIA substrates are involved in the formation of supramolecular membrane-less organelles. PPIA affects regulators of stress granules (PABPC1), P-bodies (DDX6) and nucleoli (NPM1) to promote phase separation and increase cellular stress resistance. Haematopoietic stem cell ageing is associated with a post-transcriptional decrease in PPIA expression and reduced translation of IDR-rich proteins. Here we link the chaperone PPIA to the synthesis of intrinsically disordered proteins, which indicates that impaired protein interaction networks and macromolecular condensation may be potential determinants of haematopoietic stem cell ageing.
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Biochemical Phenomena, Metabolism, and Nutrition Commons, Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Medical Biochemistry Commons, Medical Specialties Commons
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