Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death
Functional genetic screen of human diversity reveals that a methionine salvage enzyme regulates inflammatory cell death
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DOI：
10.1073/pnas.1206701109
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发表时间：
2012-08-28
影响因子：
11.1
通讯作者：
Miller, Samuel I.
中科院分区：
文献类型：
--
作者：
Ko, Dennis C.;Gamazon, Eric R.;Miller, Samuel I.
全基因组关联研究可以识别导致人类表型多样性和疾病的共同差异。当全基因组关联研究与测试变异如何改变生理学的方法相结合时，生物学见解就会出现。在这里，我们使用这种方法来揭示蛋氨酸挽救途径对细胞死亡的调节。一种常见的 SNP 与推定的蛋氨酸补救途径脱水酶、凋亡蛋白酶激活因子 1 (APAF1) 相互作用蛋白 (APIP) 表达减少相关，与沙门氏菌反应中 caspase-1 介导的细胞死亡增加相关。 APIP 在蛋氨酸回收中的作用通过使用缺乏蛋氨酸的培养基进行生长测定和蛋氨酸回收底物 5'-甲硫腺苷的定量来证实。减少 APIP 的表达或外源添加 5'-甲硫腺苷会增加沙门氏菌诱导的细胞死亡。与 APIP 最初被确定为 caspase-9 依赖性细胞凋亡抑制剂一致，相同的等位基因也与化疗药物卡铂的敏感性增加相关。我们的结果表明，影响单个基因表达的常见人类变异可以改变对两种不同细胞死亡程序的易感性。此外，促进细胞死亡的相同等位基因与全身炎症反应综合征个体的生存改善相关，这表明可能存在进化压力，可以解释观察到的该 SNP 频率的地理模式。我们的研究表明，疾病相关性状的体外关联筛选不仅可以揭示导致疾病的人类遗传差异，还可以为细胞生物学提供意想不到的见解。
Genome-wide association studies can identify common differences that contribute to human phenotypic diversity and disease. When genome-wide association studies are combined with approaches that test how variants alter physiology, biological insights can emerge. Here, we used such an approach to reveal regulation of cell death by the methionine salvage pathway. A common SNP associated with reduced expression of a putative methionine salvage pathway dehydratase, apoptotic protease activating factor 1 (APAF1)-interacting protein (APIP), was associated with increased caspase-1-mediated cell death in response to Salmonella. The role of APIP in methionine salvage was confirmed by growth assays with methionine-deficient media and quantitation of the methionine salvage substrate, 5'-methylthioadenosine. Reducing expression of APIP or exogenous addition of 5'-methylthioadenosine increased Salmonellae-induced cell death. Consistent with APIP originally being identified as an inhibitor of caspase-9-dependent apoptosis, the same allele was also associated with increased sensitivity to the chemotherapeutic agent carboplatin. Our results show that common human variation affecting expression of a single gene can alter susceptibility to two distinct cell death programs. Furthermore, the same allele that promotes cell death is associated with improved survival of individuals with systemic inflammatory response syndrome, suggesting a possible evolutionary pressure that may explain the geographic pattern observed for the frequency of this SNP. Our study shows that in vitro association screens of disease-related traits can not only reveal human genetic differences that contribute to disease but also provide unexpected insights into cell biology.