Allelic-Specific Regulation of xCT Expression Increases Susceptibility to Tuberculosis by Modulating microRNA-mRNA Interactions-猫眼课题宝

xCT 表达的等位基因特异性调节通过调节 microRNA-mRNA 相互作用增加结核病的易感性

DOI：

10.1128/msphere.00263-20

发表时间：

2020-03-01

期刊：

MSPHERE

影响因子：

4.8

通讯作者：

中科院分区：

生物学2区

文献类型：

--

作者：

Wang, Wenfei;Cai, Yi;Chen, Xinchun

结核病（TB）是全球单一传染源导致死亡的主要原因，多药耐药性的发展是一个严重的健康问题，特别是在发展中国家。迫切需要新的有效治疗方法。已知xCT表达会增加对TB的易感性，并且编码该蛋白质的基因中的某些多态性会中断microRNA的结合并阻止其抑制。利用FDA批准使用柳氮磺胺吡啶（SASP），它抑制xCT介导的胱氨酸转运在人类中，我们证明了宿主基因型特异性治疗定制的xCT基因型可以改善结核病的结果。摘要xCT是xc−半胱氨酸-谷氨酸反向转运蛋白的一部分，它抑制抗微生物炎症免疫功能，从而增加对结核病（TB）的易感性。然而，xCT基因多态性与结核病易感性之间的关联，以及这些多态性是否调节xCT表达或影响xCT抑制剂柳氮磺胺吡啶（SASP）的治疗，尚不清楚。在本研究中，我们在一个大型中国队列中对xCT多态性进行基因分型，发现单核苷酸多态性（SNP）rs 13120371与结核病易感性相关。与GG或AG基因型相比，rs 13120371 AA基因型与TB风险增加和xCT mRNA表达水平增加密切相关。rs 13120371位于xCT基因的3′非翻译区（UTR），位于miR-142- 3 p的推定结合位点，荧光素酶报告基因分析结果表明rs 13120371 AA基因型抑制miR-42- 3 p与xCT的结合。AA基因型细胞的细菌负荷也显著高于GG基因型细胞。此外，SASP预处理减轻了AA基因型细胞的这种负担，但对GG表型细胞没有益处。总之，我们在xCT 3′ UTR区域鉴定了一个功能性SNP（rs 13120371），该SNP通过与miR-142- 3 p相互作用增加了对TB的易感性。重要性结核病（TB）是全球单一传染性病原体导致死亡的主要原因，多药耐药性的发展是一个严重的健康问题，特别是在发展中国家。迫切需要新的有效治疗方法。已知xCT表达会增加对TB的易感性，并且编码该蛋白质的基因中的某些多态性会中断microRNA的结合并阻止其抑制。利用FDA批准使用柳氮磺胺吡啶（SASP），它抑制xCT介导的胱氨酸转运在人类中，我们证明了宿主基因型特异性治疗定制的xCT基因型可以改善结核病的结果。

Tuberculosis (TB) is the leading cause of death from a single infectious agent globally, and the development of multidrug resistance represents a serious health concern, particularly in the developing world. Novel effective treatments are urgently required. xCT expression is known to increase susceptibility to TB, and certain polymorphisms in the gene encoding this protein interrupt the binding of microRNA and prevent its suppression. Taking advantage of the FDA approval for the use of sulfasalazine (SASP), which inhibits xCT-mediated cystine transport in humans, we demonstrate how host genotype-specific therapies tailored to the xCT genotype can improve TB outcomes. ABSTRACT xCT forms part of the xc− cysteine-glutamate antiporter which inhibits antimicrobial inflammatory immune functions and thus increases susceptibility to tuberculosis (TB). However, the associations between xCT gene polymorphisms and susceptibility to TB, as well as whether these modulate xCT expression or affect treatment with the xCT inhibitor sulfasalazine (SASP), are unclear. In the present study, we genotyped xCT polymorphisms in a large Chinese cohort and found that the single-nucleotide polymorphism (SNP) rs13120371 was associated with susceptibility to TB. The rs13120371 AA genotype was strongly associated with an increased risk of TB and increased xCT mRNA expression levels compared to those with the GG or AG genotype. rs13120371 is located on the 3′ untranslated (UTR) region of the xCT gene, in the putative binding site for miR-142-3p, and the results of luciferase reporter assays indicated that the rs13120371 AA genotype inhibited the binding of miR-42-3p to xCT. Bacterial burden was also significantly higher in cells with the AA genotype than in those with the GG genotype. Furthermore, pretreatment with SASP alleviated this burden in cells with the AA genotype but conferred no benefit in cells with the GG phenotype. In summary, we identified a functional SNP (rs13120371) in the xCT 3′ UTR region that increases susceptibility to TB through interacting with miR-142-3p. IMPORTANCE Tuberculosis (TB) is the leading cause of death from a single infectious agent globally, and the development of multidrug resistance represents a serious health concern, particularly in the developing world. Novel effective treatments are urgently required. xCT expression is known to increase susceptibility to TB, and certain polymorphisms in the gene encoding this protein interrupt the binding of microRNA and prevent its suppression. Taking advantage of the FDA approval for the use of sulfasalazine (SASP), which inhibits xCT-mediated cystine transport in humans, we demonstrate how host genotype-specific therapies tailored to the xCT genotype can improve TB outcomes.