Deficiency of the adaptor protein SLy1 results in a natural killer cell ribosomopathy affecting tumor clearance.
Deficiency of the adaptor protein SLy1 results in a natural killer cell ribosomopathy affecting tumor clearance.
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DOI：
10.1080/2162402x.2016.1238543
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发表时间：
2016
期刊：
影响因子：
7.2
通讯作者：
Krupnick AS
中科院分区：
文献类型：
--
作者：
Arefanian S;Schäll D;Chang S;Ghasemi R;Higashikubo R;Zheleznyak A;Guo Y;Yu J;Asgharian H;Li W;Gelman AE;Kreisel D;French AR;Zaher H;Plougastel-Douglas B;Maggi L;Yokoyama W;Beer-Hammer S;Krupnick AS
自然杀伤(NK)细胞功能强健的人患恶性肿瘤的几率较低。为了扩大我们对导致这一现象的遗传因素的理解，我们分析了抗癌和敏感品系小鼠的NK细胞。我们确定了X染色体定位接头蛋白SLy1的NK水平与癌症的免疫易感性之间的相关性。与T或B淋巴细胞不同的是，SLy1在细胞质和细胞核之间穿梭，以促进信号转导，而在NK细胞中，SLy1作为核糖体蛋白发挥作用，仅位于细胞质中。在缺乏核糖体的情况下，核糖体不稳定会导致P53介导的NK细胞衰老，并降低对恶性肿瘤的清除。NK缺陷在炎症条件下是可逆的，病毒清除不受SLy1缺陷的影响。我们的工作定义了一种以前未被认识到的X连锁核糖体病，它会导致一种特殊而微妙的NK细胞功能障碍，从而导致对癌症的免疫易感性。
Individuals with robust natural killer (NK) cell function incur lower rates of malignancies. To expand our understanding of genetic factors contributing to this phenomenon, we analyzed NK cells from cancer resistant and susceptible strains of mice. We identified a correlation between NK levels of the X-chromosome-located adaptor protein SLy1 and immunologic susceptibility to cancer. Unlike the case for T or B lymphocytes, where SLy1 shuttles between the cytoplasm and nucleus to facilitate signal transduction, in NK cells SLy1 functions as a ribosomal protein and is located solely in the cytoplasm. In its absence, ribosomal instability results in p53-mediated NK cell senescence and decreased clearance of malignancies. NK defects are reversible under inflammatory conditions and viral clearance is not impacted by SLy1 deficiency. Our work defines a previously unappreciated X-linked ribosomopathy that results in a specific and subtle NK cell dysfunction leading to immunologic susceptibility to cancer.