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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...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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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 |
Sumario: | 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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