Molecular Mechanism of Bacterial Persistence by HipA

TY - JOUR

T1 - Molecular Mechanism of Bacterial Persistence by HipA

AU - Germain, Elsa

AU - Castro-Roa, Daniel

AU - Zenkin, Nikolay

AU - Gerdes, Kenn

PY - 2013/10/24

Y1 - 2013/10/24

N2 - HipA of Escherichia coli is a eukaryote-like serine-threonine kinase that inhibits cell growth and induces persistence (multidrug tolerance). Previously, it was proposed that HipA inhibits cell growth by the phosphorylation of the essential translation factor EF-Tu. Here, we provide evidence that EF-Tu is not a target of HipA. Instead, a genetic screen reveals that the overexpression of glutamyl-tRNA synthetase (GltX) suppresses the toxicity of HipA. We show that HipA phosphorylates conserved Ser239 near the active center of GltX and inhibits aminoacylation, a unique example of an aminoacyl-tRNA synthetase being inhibited by a toxin encoded by a toxin-antitoxin locus. HipA only phosphorylates tRNAGlu-bound GltX, which is consistent with the earlier finding that the regulatory motif containing Ser239 changes configuration upon tRNA binding. These results indicate that HipA mediates persistence by the generation of "hungry" codons at the ribosomal A site that trigger the synthesis of (p)ppGpp, a hypothesis that we verify experimentally.

AB - HipA of Escherichia coli is a eukaryote-like serine-threonine kinase that inhibits cell growth and induces persistence (multidrug tolerance). Previously, it was proposed that HipA inhibits cell growth by the phosphorylation of the essential translation factor EF-Tu. Here, we provide evidence that EF-Tu is not a target of HipA. Instead, a genetic screen reveals that the overexpression of glutamyl-tRNA synthetase (GltX) suppresses the toxicity of HipA. We show that HipA phosphorylates conserved Ser239 near the active center of GltX and inhibits aminoacylation, a unique example of an aminoacyl-tRNA synthetase being inhibited by a toxin encoded by a toxin-antitoxin locus. HipA only phosphorylates tRNAGlu-bound GltX, which is consistent with the earlier finding that the regulatory motif containing Ser239 changes configuration upon tRNA binding. These results indicate that HipA mediates persistence by the generation of "hungry" codons at the ribosomal A site that trigger the synthesis of (p)ppGpp, a hypothesis that we verify experimentally.

U2 - 10.1016/j.molcel.2013.08.045

DO - 10.1016/j.molcel.2013.08.045

M3 - Journal article

C2 - 24095282

SN - 1097-2765

VL - 52

SP - 248

EP - 254

JO - Molecular Cell

JF - Molecular Cell

IS - 2

ER -