Hsp70 regulates erythropoiesis by preventing caspase-3-mediated cleavage of GATA-1
| Autor: | Joelle Kersual, Thomas Kirkegaard-Sørensen, Julie Vandekerckhove, Yael Zermati, Bruno Varet, Carmen Garrido, Michael Dussiot, Ann Zeuner, Jean-Antoine Ribeil, Séverine Coulon, Séverine Cathelin, Eric Solary, Ivan C. Moura, Olivier Hermine |
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| Rok vydání: | 2006 |
| Předmět: |
Programmed cell death
Erythroblasts Cellular differentiation Apoptosis Caspase 3 hemic and lymphatic diseases medicine Humans Immunoprecipitation Erythropoiesis GATA1 Transcription Factor HSP70 Heat-Shock Proteins Erythropoietin Transcription factor Cells Cultured Caspase Multidisciplinary biology Cell Differentiation Molecular biology biology.protein Protein Binding medicine.drug |
| Zdroj: | Nature. 445:102-105 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | Caspase-3 is activated during both terminal differentiation and erythropoietin-starvation-induced apoptosis of human erythroid precursors. The transcription factor GATA-1, which performs an essential function in erythroid differentiation by positively regulating promoters of erythroid and anti-apoptotic genes, is cleaved by caspases in erythroid precursors undergoing cell death upon erythropoietin starvation or engagement of the death receptor Fas. In contrast, by an unknown mechanism, GATA-1 remains uncleaved when these cells undergo terminal differentiation upon stimulation with Epo. Here we show that during differentiation, but not during apoptosis, the chaperone protein Hsp70 protects GATA-1 from caspase-mediated proteolysis. At the onset of caspase activation, Hsp70 co-localizes and interacts with GATA-1 in the nucleus of erythroid precursors undergoing terminal differentiation. In contrast, erythropoietin starvation induces the nuclear export of Hsp70 and the cleavage of GATA-1. In an in vitro assay, Hsp70 protects GATA-1 from caspase-3-mediated proteolysis through its peptide-binding domain. The use of RNA-mediated interference to decrease the Hsp70 content of erythroid precursors cultured in the presence of erythropoietin leads to GATA-1 cleavage, a decrease in haemoglobin content, downregulation of the expression of the anti-apoptotic protein Bcl-X(L), and cell death by apoptosis. These effects are abrogated by the transduction of a caspase-resistant GATA-1 mutant. Thus, in erythroid precursors undergoing terminal differentiation, Hsp70 prevents active caspase-3 from cleaving GATA-1 and inducing apoptosis. |
| Databáze: | OpenAIRE |
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