Site-specific acylation of a bacterial virulence regulator attenuates infection.
Site-specific acylation of a bacterial virulence regulator attenuates infection.
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DOI：
10.1038/s41589-019-0392-5
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发表时间：
2020-01
影响因子：
14.8
通讯作者：
Hang HC
中科院分区：
文献类型：
--
作者：
Zhang ZJ;Pedicord VA;Peng T;Hang HC
微生物群产生毫摩尔浓度的短链脂肪酸（SCFA），可以调节宿主的代谢，免疫力和感染易感性。丁酸盐尤其可以作为碳源和抗炎代谢物，但其抑制病原体毒力的机制一直难以捉摸。利用化学蛋白质组学方法，我们发现沙门氏菌致病岛-1（SPI-1）编码的几种毒力因子被SCFAs酰化。值得注意的是，SPI-1的转录调节因子HilA在几个关键的赖氨酸残基上被酰化。随后使用CRISPR-Cas9基因编辑和非天然氨基酸诱变掺入稳定的丁酰-赖氨酸类似物，揭示了HilA的位点特异性修饰影响其基因组占据、SPI-1基因的表达，并减弱肠道沙门氏菌鼠伤寒血清型对上皮细胞的侵袭以及体内传播。此外，还获得了一株具有多位点HilA赖氨酸酰化的S.鼠伤寒对丁酸盐介导的体内抑制具有抗性。我们的研究结果表明，微生物衍生的主要代谢产物可能直接酰化毒力因子，以抑制体内微生物的致病作用。
Microbiota generates millimolar concentrations of short-chain fatty acids (SCFAs) that can modulate host metabolism, immunity and susceptibility to infection. Butyrate in particular can function as a carbon source and anti-inflammatory metabolite, but the mechanism by which it inhibits pathogen virulence has been elusive. Using chemical proteomics, we discovered that several virulence factors encoded by Salmonella pathogenicity island-1 (SPI-1) are acylated by SCFAs. Notably, a transcriptional regulator of SPI-1, HilA, was acylated on several key lysine residues. Subsequent incorporation of stable butyryl-lysine analogs using CRISPR-Cas9 gene editing and unnatural amino acid mutagenesis revealed that site-specific modification of HilA impacts its genomic occupancy, expression of SPI-1 genes and attenuates Salmonella enterica serovar Typhimurium invasion of epithelial cells as well as dissemination in vivo. Moreover, a multiple-site HilA lysine-acylation mutant strain of S. Typhimurium was resistant to butyrate-mediated suppression in vivo. Our results suggest prominent microbiota-derived metabolites may directly acylate virulence factors to inhibit microbial pathogenesis in vivo.
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影响因子：
30.3
作者：
Jacobson A;Lam L;Rajendram M;Tamburini F;Honeycutt J;Pham T;Van Treuren W;Pruss K;Stabler SR;Lugo K;Bouley DM;Vilches-Moure JG;Smith M;Sonnenburg JL;Bhatt AS;Huang KC;Monack D
通讯作者：
Monack D
影响因子：
3.6
作者：
Hung CC;Garner CD;Slauch JM;Dwyer ZW;Lawhon SD;Frye JG;McClelland M;Ahmer BM;Altier C
通讯作者：
Altier C
影响因子：
29
作者：
Donohoe DR;Garge N;Zhang X;Sun W;O'Connell TM;Bunger MK;Bultman SJ
通讯作者：
Bultman SJ
DOI：
10.1126/science.aam9949
发表时间：
2017-08-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Byndloss MX;Olsan EE;Rivera-Chávez F;Tiffany CR;Cevallos SA;Lokken KL;Torres TP;Byndloss AJ;Faber F;Gao Y;Litvak Y;Lopez CA;Xu G;Napoli E;Giulivi C;Tsolis RM;Revzin A;Lebrilla CB;Bäumler AJ
通讯作者：
Bäumler AJ
影响因子：
30.3
作者：
Bronner DN;Faber F;Olsan EE;Byndloss MX;Sayed NA;Xu G;Yoo W;Kim D;Ryu S;Lebrilla CB;Bäumler AJ
通讯作者：
Bäumler AJ