Cyclophilin A supports translation of intrinsically disordered proteins and affects haematopoietic stem cell ageing
Open accessPublished version of a preprint
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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- Authors
- Maneix, L., Iakova, P., Lee, C. G., Moree, S. E., Lu, X., Datar, G. K., Hill, C. T., Spooner, E., King, J. C. K., Sykes, D. B., Saez, B., Di Stefano, B., Chen, X., Krause, D. S., Sahin, E., Tsai, F. T. F., Goodell, M. A., Berk, B. C., Scadden, D. T., & Catic, A.
- Affiliations
- Baylor College of Medicine (US)
- Rice University (US)
- Harvard University (US)
- Whitehead Institute for Biomedical Research (US)
- Georg Speyer Haus (DE)
- University of Rochester Medicine (US)
- Michael E. DeBakey VA Medical Center (US)
- Corresponding author
- Catic, André
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2024-03-29
- Volume
- 26
- Issue
- 4
- Pages
- 593-603
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC11021199
- OpenAlex
- W4393317394
- Cited by
- 28
- References
- 8
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 4 · 2023: 2 · 2022: 1
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Cell Biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R01DK115454, 2T32DK060445)
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R01GM142143)
- American Society of Hematology (Bridge Grant 2023)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- cyclophilin A, peptidyl-prolyl isomerase, intrinsically disordered regions, mRNA translation, molecular chaperones, liquid-liquid phase separation, biomolecular condensates, stress granules, PABPC1, P-bodies, DDX6, nucleolus, NPM1, post-transcriptional regulation, cellular stress resistance, protein-protein interaction network
- MeSH terms
- Hematopoietic Stem Cells, RNA-Binding Proteins, Cyclophilin A, Intrinsically Disordered Proteins
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