Skip to Main content Skip to Navigation
Journal articles

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

Abstract : Lymphocyte functions triggered by antigen recognition and co-stimulation signals are associated with a rapid and intense cell division, and hence with metabolism adaptation. The nucleotide cytidine 5' triphosphate (CTP) is a precursor required for the metabolism of DNA, RNA and phospholipids. CTP originates from two sources: a salvage pathway and a de novo synthesis pathway that depends on two enzymes, the CTP synthases (or synthetases) 1 and 2 (CTPS1 with CTPS2); the respective roles of these two enzymes are not known. CTP synthase activity is a potentially important step for DNA synthesis in lymphocytes. Here we report the identification of a loss-of-function homozygous mutation (rs145092287) in CTPS1 in humans that causes 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 T-cell receptor (TCR) signalling events and responses were only weakly affected by the absence of CTPS1. Activated CTPS1-deficient cells had 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.
Document type :
Journal articles
Complete list of metadatas
Contributor : Sarah Adele <>
Submitted on : Tuesday, July 23, 2019 - 3:23:35 PM
Last modification on : Wednesday, June 10, 2020 - 12:50:59 PM

Links full text



E. Martin, N. Palmic, S. Sanquer, C. Lenoir, F. Hauck, et al.. CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation. Nature, Nature Publishing Group, 2014, 510 (7504), pp.288--92. ⟨10.1038/nature13386⟩. ⟨hal-02191580⟩



Record views