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Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival
Neutrophil apoptosis is a highly regulated process essential for inflammation resolution, the molecular mechanisms of which are only partially elucidated. In this study, we describe a survival pathway controlled by proliferating cell nuclear antigen (PCNA), a nuclear factor involved in DNA replicati...
Autores principales: | , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989777/ https://www.ncbi.nlm.nih.gov/pubmed/20975039 http://dx.doi.org/10.1084/jem.20092241 |
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author | Witko-Sarsat, Véronique Mocek, Julie Bouayad, Dikra Tamassia, Nicola Ribeil, Jean-Antoine Candalh, Céline Davezac, Noélie Reuter, Nathalie Mouthon, Luc Hermine, Olivier Pederzoli-Ribeil, Magali Cassatella, Marco A. |
author_facet | Witko-Sarsat, Véronique Mocek, Julie Bouayad, Dikra Tamassia, Nicola Ribeil, Jean-Antoine Candalh, Céline Davezac, Noélie Reuter, Nathalie Mouthon, Luc Hermine, Olivier Pederzoli-Ribeil, Magali Cassatella, Marco A. |
author_sort | Witko-Sarsat, Véronique |
collection | PubMed |
description | Neutrophil apoptosis is a highly regulated process essential for inflammation resolution, the molecular mechanisms of which are only partially elucidated. In this study, we describe a survival pathway controlled by proliferating cell nuclear antigen (PCNA), a nuclear factor involved in DNA replication and repairing of proliferating cells. We show that mature neutrophils, despite their inability to proliferate, express high levels of PCNA exclusively in their cytosol and constitutively associated with procaspases, presumably to prevent their activation. Notably, cytosolic PCNA abundance decreased during apoptosis, and increased during in vitro and in vivo exposure to the survival factor granulocyte colony-stimulating factor (G-CSF). Peptides derived from the cyclin-dependent kinase inhibitor p21, which compete with procaspases to bind PCNA, triggered neutrophil apoptosis thus demonstrating that specific modification of PCNA protein interactions affects neutrophil survival. Furthermore, PCNA overexpression rendered neutrophil-differentiated PLB985 myeloid cells significantly more resistant to TNF-related apoptosis-inducing ligand– or gliotoxin-induced apoptosis. Conversely, a decrease in PCNA expression after PCNA small interfering RNA transfection sensitized these cells to apoptosis. Finally, a mutation in the PCNA interdomain-connecting loop, the binding site for many partners, significantly decreased the PCNA-mediated antiapoptotic effect. These results identify PCNA as a regulator of neutrophil lifespan, thereby highlighting a novel target to potentially modulate pathological inflammation. |
format | Text |
id | pubmed-2989777 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-29897772011-05-22 Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival Witko-Sarsat, Véronique Mocek, Julie Bouayad, Dikra Tamassia, Nicola Ribeil, Jean-Antoine Candalh, Céline Davezac, Noélie Reuter, Nathalie Mouthon, Luc Hermine, Olivier Pederzoli-Ribeil, Magali Cassatella, Marco A. J Exp Med Article Neutrophil apoptosis is a highly regulated process essential for inflammation resolution, the molecular mechanisms of which are only partially elucidated. In this study, we describe a survival pathway controlled by proliferating cell nuclear antigen (PCNA), a nuclear factor involved in DNA replication and repairing of proliferating cells. We show that mature neutrophils, despite their inability to proliferate, express high levels of PCNA exclusively in their cytosol and constitutively associated with procaspases, presumably to prevent their activation. Notably, cytosolic PCNA abundance decreased during apoptosis, and increased during in vitro and in vivo exposure to the survival factor granulocyte colony-stimulating factor (G-CSF). Peptides derived from the cyclin-dependent kinase inhibitor p21, which compete with procaspases to bind PCNA, triggered neutrophil apoptosis thus demonstrating that specific modification of PCNA protein interactions affects neutrophil survival. Furthermore, PCNA overexpression rendered neutrophil-differentiated PLB985 myeloid cells significantly more resistant to TNF-related apoptosis-inducing ligand– or gliotoxin-induced apoptosis. Conversely, a decrease in PCNA expression after PCNA small interfering RNA transfection sensitized these cells to apoptosis. Finally, a mutation in the PCNA interdomain-connecting loop, the binding site for many partners, significantly decreased the PCNA-mediated antiapoptotic effect. These results identify PCNA as a regulator of neutrophil lifespan, thereby highlighting a novel target to potentially modulate pathological inflammation. The Rockefeller University Press 2010-11-22 /pmc/articles/PMC2989777/ /pubmed/20975039 http://dx.doi.org/10.1084/jem.20092241 Text en © 2010 Witko-Sarsat et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Article Witko-Sarsat, Véronique Mocek, Julie Bouayad, Dikra Tamassia, Nicola Ribeil, Jean-Antoine Candalh, Céline Davezac, Noélie Reuter, Nathalie Mouthon, Luc Hermine, Olivier Pederzoli-Ribeil, Magali Cassatella, Marco A. Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival |
title | Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival |
title_full | Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival |
title_fullStr | Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival |
title_full_unstemmed | Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival |
title_short | Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival |
title_sort | proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989777/ https://www.ncbi.nlm.nih.gov/pubmed/20975039 http://dx.doi.org/10.1084/jem.20092241 |
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