HipA-mediated antibiotic persistence via phosphorylation of the glutamyl-tRNA-synthetase
HipA-mediated antibiotic persistence via phosphorylation of the glutamyl-tRNA-synthetase
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DOI：
10.1038/ncomms4001
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发表时间：
2013-12-01
影响因子：
16.6
通讯作者：
Glaser, Gad
中科院分区：
文献类型：
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作者：
Kaspy, Ilana;Rotem, Eitan;Glaser, Gad
细菌的持久性已被证明是抗生素治疗失败的一个潜在因素。尽管包括严格反应和毒素-抗毒素模块在内的许多途径都与抗生素持久性有关，但持久性细菌生长受阻的明确分子机制仍然难以捉摸。在这里，我们筛选了HipA的可能靶点的表达文库，HipA是第一种与持久性有关的毒素，以及丝氨酸/苏氨酸激酶。我们发现，谷氨酰tRNA合成酶GltX的表达逆转了HipA的毒性，并阻止了持久蛋白的形成。我们发现，在HipA表达的基础上，GltX在其ATP结合位点Ser239处经历了磷酸化。这种磷酸化导致不带电荷的tRNA(Glu)在细胞内积累，从而激活严格的反应。我们的发现证明了HipBA毒素-抗毒素模块形成持久性的机制，并为长期观察到的持久性和严格反应之间的联系提供了解释。
Bacterial persistence has been shown to be an underlying factor in the failure of antibiotic treatments. Although many pathways, among them the stringent response and toxin-antitoxin modules, have been linked to antibiotic persistence, a clear molecular mechanism for the growth arrest that characterizes persistent bacteria remained elusive. Here, we screened an expression library for putative targets of HipA, the first toxin linked to persistence, and a serine/threonine kinase. We found that the expression of GltX, the glutamyl-tRNA-synthetase, reverses the toxicity of HipA and prevents persister formation. We show that upon HipA expression, GltX undergoes phosphorylation at Ser239, its ATP-binding site. This phosphorylation leads to accumulation of uncharged tRNA(Glu) in the cell, which results in the activation of the stringent response. Our findings demonstrate a mechanism for persister formation by the hipBA toxin-antitoxin module and provide an explanation for the long-observed connection between persistence and the stringent response.