PTBP1 promotes hematopoietic stem cell maintenance and red blood cell development by ensuring sufficient availability of ribosomal constituents
Ribosomopathies constitute a range of disorders associated with defective protein synthesis mainly affecting hematopoietic stem cells (HSCs) and erythroid development. Here, we demonstrate that deletion of poly-pyrimidine-tract-binding protein 1 (PTBP1) in the hematopoietic compartment leads to the...
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| Veröffentlicht in: | Cell reports (Cambridge) 2022-05, Vol.39 (6), p.110793-110793, Article 110793 |
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| creator | Rehn, Matilda Wenzel, Anne Frank, Anne-Katrine Schuster, Mikkel Bruhn Pundhir, Sachin Jørgensen, Nanna Vitting-Seerup, Kristoffer Ge, Ying Jendholm, Johan Michaut, Magali Schoof, Erwin M Jensen, Tanja Lyholm Rapin, Nicolas Sapio, Russell T Andersen, Kasper Langebjerg Lund, Anders H Solimena, Michele Holzenberger, Martin Pestov, Dimitri G Porse, Bo Torben |
| description | Ribosomopathies constitute a range of disorders associated with defective protein synthesis mainly affecting hematopoietic stem cells (HSCs) and erythroid development. Here, we demonstrate that deletion of poly-pyrimidine-tract-binding protein 1 (PTBP1) in the hematopoietic compartment leads to the development of a ribosomopathy-like condition. Specifically, loss of PTBP1 is associated with decreases in HSC self-renewal, erythroid differentiation, and protein synthesis. Consistent with its function as a splicing regulator, PTBP1 deficiency results in splicing defects in hundreds of genes, and we demonstrate that the up-regulation of a specific isoform of CDC42 partly mimics the protein-synthesis defect associated with loss of PTBP1. Furthermore, PTBP1 deficiency is associated with a marked defect in ribosome biogenesis and a selective reduction in the translation of mRNAs encoding ribosomal proteins. Collectively, this work identifies PTBP1 as a key integrator of ribosomal functions and highlights the broad functional repertoire of RNA-binding proteins. |
| doi_str_mv | 10.1016/j.celrep.2022.110793 |
| format | Article |
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Here, we demonstrate that deletion of poly-pyrimidine-tract-binding protein 1 (PTBP1) in the hematopoietic compartment leads to the development of a ribosomopathy-like condition. Specifically, loss of PTBP1 is associated with decreases in HSC self-renewal, erythroid differentiation, and protein synthesis. Consistent with its function as a splicing regulator, PTBP1 deficiency results in splicing defects in hundreds of genes, and we demonstrate that the up-regulation of a specific isoform of CDC42 partly mimics the protein-synthesis defect associated with loss of PTBP1. Furthermore, PTBP1 deficiency is associated with a marked defect in ribosome biogenesis and a selective reduction in the translation of mRNAs encoding ribosomal proteins. Collectively, this work identifies PTBP1 as a key integrator of ribosomal functions and highlights the broad functional repertoire of RNA-binding proteins.</description><identifier>ISSN: 2211-1247</identifier><identifier>EISSN: 2211-1247</identifier><identifier>DOI: 10.1016/j.celrep.2022.110793</identifier><identifier>PMID: 35545054</identifier><language>eng</language><publisher>United States</publisher><subject>Erythrocytes - metabolism ; Erythropoiesis ; Hematopoietic Stem Cells - metabolism ; Heterogeneous-Nuclear Ribonucleoproteins - genetics ; Heterogeneous-Nuclear Ribonucleoproteins - metabolism ; Polypyrimidine Tract-Binding Protein - genetics ; Polypyrimidine Tract-Binding Protein - metabolism ; Ribosomal Proteins - metabolism ; Ribosomes - metabolism</subject><ispartof>Cell reports (Cambridge), 2022-05, Vol.39 (6), p.110793-110793, Article 110793</ispartof><rights>Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-addd2390b2c0e0594430dbc33d6b30743622032c2f384f7e84df269b0e07f83</citedby><cites>FETCH-LOGICAL-c353t-addd2390b2c0e0594430dbc33d6b30743622032c2f384f7e84df269b0e07f83</cites><orcidid>0000-0002-9436-9655 ; 0000-0001-6043-0844 ; 0000-0002-6450-0608 ; 0000-0001-6635-6104 ; 0000-0002-7407-3398 ; 0000-0002-5127-113X ; 0000-0003-2002-2277 ; 0000-0002-1425-9879</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,860,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35545054$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rehn, Matilda</creatorcontrib><creatorcontrib>Wenzel, Anne</creatorcontrib><creatorcontrib>Frank, Anne-Katrine</creatorcontrib><creatorcontrib>Schuster, Mikkel Bruhn</creatorcontrib><creatorcontrib>Pundhir, Sachin</creatorcontrib><creatorcontrib>Jørgensen, Nanna</creatorcontrib><creatorcontrib>Vitting-Seerup, Kristoffer</creatorcontrib><creatorcontrib>Ge, Ying</creatorcontrib><creatorcontrib>Jendholm, Johan</creatorcontrib><creatorcontrib>Michaut, Magali</creatorcontrib><creatorcontrib>Schoof, Erwin M</creatorcontrib><creatorcontrib>Jensen, Tanja Lyholm</creatorcontrib><creatorcontrib>Rapin, Nicolas</creatorcontrib><creatorcontrib>Sapio, Russell T</creatorcontrib><creatorcontrib>Andersen, Kasper Langebjerg</creatorcontrib><creatorcontrib>Lund, Anders H</creatorcontrib><creatorcontrib>Solimena, Michele</creatorcontrib><creatorcontrib>Holzenberger, Martin</creatorcontrib><creatorcontrib>Pestov, Dimitri G</creatorcontrib><creatorcontrib>Porse, Bo Torben</creatorcontrib><title>PTBP1 promotes hematopoietic stem cell maintenance and red blood cell development by ensuring sufficient availability of ribosomal constituents</title><title>Cell reports (Cambridge)</title><addtitle>Cell Rep</addtitle><description>Ribosomopathies constitute a range of disorders associated with defective protein synthesis mainly affecting hematopoietic stem cells (HSCs) and erythroid development. Here, we demonstrate that deletion of poly-pyrimidine-tract-binding protein 1 (PTBP1) in the hematopoietic compartment leads to the development of a ribosomopathy-like condition. Specifically, loss of PTBP1 is associated with decreases in HSC self-renewal, erythroid differentiation, and protein synthesis. Consistent with its function as a splicing regulator, PTBP1 deficiency results in splicing defects in hundreds of genes, and we demonstrate that the up-regulation of a specific isoform of CDC42 partly mimics the protein-synthesis defect associated with loss of PTBP1. Furthermore, PTBP1 deficiency is associated with a marked defect in ribosome biogenesis and a selective reduction in the translation of mRNAs encoding ribosomal proteins. 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| ispartof | Cell reports (Cambridge), 2022-05, Vol.39 (6), p.110793-110793, Article 110793 |
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| subjects | Erythrocytes - metabolism Erythropoiesis Hematopoietic Stem Cells - metabolism Heterogeneous-Nuclear Ribonucleoproteins - genetics Heterogeneous-Nuclear Ribonucleoproteins - metabolism Polypyrimidine Tract-Binding Protein - genetics Polypyrimidine Tract-Binding Protein - metabolism Ribosomal Proteins - metabolism Ribosomes - metabolism |
| title | PTBP1 promotes hematopoietic stem cell maintenance and red blood cell development by ensuring sufficient availability of ribosomal constituents |
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