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CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation

Lymphocyte functions triggered by antigen recognition and cosignals imply rapid and intense cell division, hence metabolism adaptation(1). The cytidine nucleotide triphosphate (CTP) is a precursor required for the metabolism of DNA, RNA and phospholipids(2-4). CTP originates from two sources: a salv...

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Autores principales: Martin, Emmanuel, Palmic, Noé, Sanquer, Sylvia, Lenoir, Christelle, Hauck, Fabian, Mongellaz, Cédric, Fabrega, Sylvie, Nitschké, Patrick, Esposti, Mauro Degli, Schwartzentruber, Jeremy, Taylor, Naomi, Majewski, Jacek, Jabado, Nada, Wynn, Robert, Picard, Capucine, Fischer, Alain, Arkwright, Peter, Latour, Sylvain
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485470/
https://www.ncbi.nlm.nih.gov/pubmed/24870241
http://dx.doi.org/10.1038/nature13386
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author Martin, Emmanuel
Palmic, Noé
Sanquer, Sylvia
Lenoir, Christelle
Hauck, Fabian
Mongellaz, Cédric
Fabrega, Sylvie
Nitschké, Patrick
Esposti, Mauro Degli
Schwartzentruber, Jeremy
Taylor, Naomi
Majewski, Jacek
Jabado, Nada
Wynn, Robert
Picard, Capucine
Fischer, Alain
Arkwright, Peter
Latour, Sylvain
author_facet Martin, Emmanuel
Palmic, Noé
Sanquer, Sylvia
Lenoir, Christelle
Hauck, Fabian
Mongellaz, Cédric
Fabrega, Sylvie
Nitschké, Patrick
Esposti, Mauro Degli
Schwartzentruber, Jeremy
Taylor, Naomi
Majewski, Jacek
Jabado, Nada
Wynn, Robert
Picard, Capucine
Fischer, Alain
Arkwright, Peter
Latour, Sylvain
author_sort Martin, Emmanuel
collection PubMed
description Lymphocyte functions triggered by antigen recognition and cosignals imply rapid and intense cell division, hence metabolism adaptation(1). The cytidine nucleotide triphosphate (CTP) is a precursor required for the metabolism of DNA, RNA and phospholipids(2-4). CTP originates from two sources: a salvage pathway and a de novo synthesis pathway that depends on two enzymes, the CTP synthase (or synthetase) 1 and 2 (CTPS1 and CTPS2), although their respective roles are not known(5-7). CTP synthase activity is a potentially important step for DNA synthesis in lymphocytes(8, 9). Here, we report the identification of a loss of function homozygous mutation (rs145092287) in CTPS1 in humans causing a novel and life threatening immunodeficiency characterized by an impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation. In contrast, proximal and distal TCR signaling events and responses were only weakly affected by the absence of CTPS1. Activated CTPS1-deficient cells exhibited decreased levels of CTP. Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by addition of exogenous CTP or its nucleoside precursor, cytidine. CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following TCR activation. These results highlight a key and specific role of CTPS1 in the immune system by its capacity to sustain the proliferation of activated lymphocytes during the immune response. CTPS1 may therefore represent a therapeutic target of immunosuppressive drugs that could specifically dampen lymphocyte activation.
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spelling pubmed-64854702019-04-26 CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation Martin, Emmanuel Palmic, Noé Sanquer, Sylvia Lenoir, Christelle Hauck, Fabian Mongellaz, Cédric Fabrega, Sylvie Nitschké, Patrick Esposti, Mauro Degli Schwartzentruber, Jeremy Taylor, Naomi Majewski, Jacek Jabado, Nada Wynn, Robert Picard, Capucine Fischer, Alain Arkwright, Peter Latour, Sylvain Nature Article Lymphocyte functions triggered by antigen recognition and cosignals imply rapid and intense cell division, hence metabolism adaptation(1). The cytidine nucleotide triphosphate (CTP) is a precursor required for the metabolism of DNA, RNA and phospholipids(2-4). CTP originates from two sources: a salvage pathway and a de novo synthesis pathway that depends on two enzymes, the CTP synthase (or synthetase) 1 and 2 (CTPS1 and CTPS2), although their respective roles are not known(5-7). CTP synthase activity is a potentially important step for DNA synthesis in lymphocytes(8, 9). Here, we report the identification of a loss of function homozygous mutation (rs145092287) in CTPS1 in humans causing a novel and life threatening immunodeficiency characterized by an impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation. In contrast, proximal and distal TCR signaling events and responses were only weakly affected by the absence of CTPS1. Activated CTPS1-deficient cells exhibited decreased levels of CTP. Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by addition of exogenous CTP or its nucleoside precursor, cytidine. CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following TCR activation. These results highlight a key and specific role of CTPS1 in the immune system by its capacity to sustain the proliferation of activated lymphocytes during the immune response. CTPS1 may therefore represent a therapeutic target of immunosuppressive drugs that could specifically dampen lymphocyte activation. 2014-05-28 2014-06-12 /pmc/articles/PMC6485470/ /pubmed/24870241 http://dx.doi.org/10.1038/nature13386 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Martin, Emmanuel
Palmic, Noé
Sanquer, Sylvia
Lenoir, Christelle
Hauck, Fabian
Mongellaz, Cédric
Fabrega, Sylvie
Nitschké, Patrick
Esposti, Mauro Degli
Schwartzentruber, Jeremy
Taylor, Naomi
Majewski, Jacek
Jabado, Nada
Wynn, Robert
Picard, Capucine
Fischer, Alain
Arkwright, Peter
Latour, Sylvain
CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation
title CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation
title_full CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation
title_fullStr CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation
title_full_unstemmed CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation
title_short CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation
title_sort ctp synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485470/
https://www.ncbi.nlm.nih.gov/pubmed/24870241
http://dx.doi.org/10.1038/nature13386
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