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摘要 : 法国内克尔儿童组织Malades医院等处的研究人员发现,酶CTPS1的缺失(一种人类免疫缺陷的基础形式)显示出了在免疫应答中的代谢中起作用,说明这种酶是适应性免疫中的一个关键的检查点,可用于作为用于治疗疾病的一个目标,如白血病。相关文章发表于2014年5月28日的《Nature》杂志上。


编码“胞苷-5ʹ-三磷酸合酶-1”(CTPS1)的基因所发生的丧失功能突变与在抗原刺激后发生的T-细胞增殖受到的严重和选择性受损有关,说明这种酶是适应性免疫中的一个关键的检查点。CTPS1 缺失不会诱导其他表型异常,所以这些发现说明CTPS1 可以是用来抑制不想要的适应性反应的治疗药物的一个可行目标。


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

Emmanuel Martin, Noé Palmic, Sylvia Sanquer, Christelle Lenoir, Fabian Hauck, Cédric Mongellaz, Sylvie Fabrega, Patrick Nitschké, Mauro Degli Esposti, Jeremy Schwartzentruber, Naomi Taylor, Jacek Majewski, Nada Jabado, Robert F. Wynn, Capucine Picard, Alain Fischer, Peter D. Arkwright & Sylvain Latour

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.

对应Nature杂志: 2014年6月12日Nature杂志精选

来源: Nature中文 浏览次数:158


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