Identification of a Bile Acid-Binding Transcription Factor in Clostridioides difficile Using Chemical Proteomics.
Identification of a Bile Acid-Binding Transcription Factor in Clostridioides difficile Using Chemical Proteomics.
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DOI：
10.1021/acschembio.2c00463
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发表时间：
2022-11-18
影响因子：
4
通讯作者：
Shen, Aimee
中科院分区：
文献类型：
--
作者：
Forster, Emily R.;Yang, Xinglin;Tai, Albert K.;Hang, Howard C.;Shen, Aimee
艰难梭菌是一种革兰氏阳性厌氧菌，是美国医院获得性胃肠炎的主要原因。在肠道环境中，C.艰难梭菌遇到微生物群来源的生长抑制胆汁酸，其被认为是定植抗性的重要机制。而肠道中某些胆汁酸的水平与对C.艰难梭菌感染，其分子靶点在C.困难仍然未知。在这项研究中，我们试图使用化学蛋白质组学来确定胆汁酸相互作用蛋白质在C。很难使用光亲和胆汁酸探针和化学蛋白质组学，我们确定了以前未表征的MerR家族蛋白，CD 3583（现在BapR），作为一个假定的胆汁酸敏感转录调节。我们的数据表明，BapR特异性结合并稳定的石胆酸（LCA）在C。很难虽然BapR的缺失对C.由于艰难梭菌对LCA的敏感性，与野生型细胞相比，在LCA存在下ΔbapR细胞伸长更多。转录组学显示，BapR调节几个基因簇，在LCA的存在下，以BapR依赖的方式特异性去抑制mdeA-cd 3573位点的表达。电泳迁移率变动分析表明，BapR直接结合到mdeA启动子区。由于mdeA参与氨基酸相关的硫代谢和mdeA-cd 3573位点编码推定的转运蛋白，我们建议，BapR的感官胃肠道特异性小分子，LCA，作为环境的线索代谢适应。
Clostridioides difficile is a Gram-positive anaerobic bacterium that is the leading cause of hospital-acquired gastro-enteritis in the US. In the gut milieu, C. difficile encounters microbiota-derived, growth-inhibiting bile acids that are thought to be a significant mechanism of colonization resistance. While the levels of certain bile acids in the gut correlate with susceptibility to C. difficile infection, their molecular targets in C. difficile remain unknown. In this study, we sought to use chemical proteomics to identify bile acid-interacting proteins in C. difficile. Using photoaffinity bile acid probes and chemical proteomics, we identified a previously uncharacterized MerR family protein, CD3583 (now BapR), as a putative bile acid-sensing transcription regulator. Our data indicate that BapR specifically binds to and is stabilized by lithocholic acid (LCA) in C. difficile. Although loss of BapR did not affect C. difficile’s sensitivity to LCA, ΔbapR cells elongated more in the presence of LCA compared to wild-type cells. Transcriptomics revealed that BapR regulates several gene clusters, with the expression of the mdeA-cd3573 locus being specifically de-repressed in the presence of LCA in a BapR-dependent manner. Electrophoretic mobility shift assays revealed that BapR directly binds to the mdeA promoter region. Because mdeA is involved in amino acid-related sulfur metabolism and the mdeA-cd3573 locus encodes putative transporters, we propose that BapR senses a gastrointestinal tract-specific small molecule, LCA, as an environmental cue for metabolic adaptation.
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美国梭菌艰难梭菌感染和结果负担的趋势。
DOI：
10.1056/nejmoa1910215
发表时间：
2020-04-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guh AY;Mu Y;Winston LG;Johnston H;Olson D;Farley MM;Wilson LE;Holzbauer SM;Phipps EC;Dumyati GK;Beldavs ZG;Kainer MA;Karlsson M;Gerding DN;McDonald LC;Emerging Infections Program Clostridioides difficile Infection Working Group
通讯作者：
Emerging Infections Program Clostridioides difficile Infection Working Group
影响因子：
14.9
作者：
Chang CC;Lin LY;Zou XW;Huang CC;Chan NL
通讯作者：
Chan NL
影响因子：
8
作者：
Kabir, Aurangazeb;Honda, Ryo P.;Kamatari, Yuji O.;Endo, Satoshi;Fukuoka, Mayuko;Kuwata, Kazuo
通讯作者：
Kuwata, Kazuo
DOI：
10.1152/ajpgi.00027.2007
发表时间：
2007-07-01
影响因子：
4.5
作者：
Hamilton, James P.;Xie, Guofeng;Hofmann, Alan F.
通讯作者：
Hofmann, Alan F.
影响因子：
3.2
作者：
Beggs, Grace A.;Zalucki, Yaramah M.;Brennan, Richard G.
通讯作者：
Brennan, Richard G.