HipA-mediated antibiotic persistence via phosphorylation of the glutamyl-tRNA-synthetase

Ilana Kaspy, Eitan Rotem, Noga Weiss, Irine Ronin, Nathalie Q. Balaban, Gad Glaser*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

191 Scopus citations


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 tRNAGlu 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.

Original languageAmerican English
Article number3001
JournalNature Communications
StatePublished - 17 Dec 2013

Bibliographical note

Funding Information:
We thank Hila Wolf-Levi from the Selmor Proteomics Center in the Haifa University, for the MS-MS analysis; Ofra Moshel and Alex Eliassaf Feldstein for helping the MS-MS interpretations. Yoav Smith for statistical assistance. NQB is supported by the European Research Council grant no. 260871. G.G. and N.Q.B. acknowledge funding of the Israel Science Foundation grant no. 374/08 and no. 592/10, respectively.


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