Abstract

ABSTRACTBacterial cells utilize toxin-antitoxin systems to inhibit self-reproduction, while maintaining viability, when faced with environmental challenges. The activation of the toxin is often coupled to the induction of cellular response pathways, such as the stringent response, in response to multiple stress conditions. Under these conditions, the cell enters a quiescent state referred to as dormancy or persistence. How toxin activation triggers persistence and induces a systemic stress response in the alphaproteobacteria remains unclear. Here, we report that in Caulobacter, a hipA2-encoded bacterial toxin contributes to bacterial persistence by manipulating intracellular amino acid balance. HipA2 is a serine/threonine kinase that deactivates tryptophanyl-tRNA synthetase by phosphorylation, leading to stalled protein synthesis and the accumulation of free tryptophan. An increased level of tryptophan allosterically activates the adenylyltransferase activity of GlnE that, in turn, deactivates glutamine synthetase GlnA by adenylylation. The inactivation of GlnA promotes the deprivation of glutamine in the cell, which triggers a stringent response. By screening 69 stress conditions, we find that HipBA2 responds to multiple stress signals through the proteolysis of HipB2 antitoxin by the Lon protease and the release of active HipA2 kinase, revealing a molecular mechanism that allows disparate stress conditions to be sensed and funneled into a single response pathway.

Highlights

  • Bacterial cells utilize toxin-antitoxin systems to inhibit self-reproduction, while maintaining viability, when faced with environmental challenges

  • We discovered that the HipA2 toxin in Caulobacter induces bacterial persistence and (p)ppGpp accumulation by disturbing intracellular tryptophan-glutamine balance

  • HipBA toxin-antitoxin modules have been discovered in multiple bacteria [15]

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Summary

Introduction

Bacterial cells utilize toxin-antitoxin systems to inhibit self-reproduction, while maintaining viability, when faced with environmental challenges. The activation of the toxin is often coupled to the induction of cellular response pathways, such as the stringent response, in response to multiple stress conditions Under these conditions, the cell enters a quiescent state referred to as dormancy or persistence. By screening 69 stress conditions, we find that HipBA2 responds to multiple stress signals through the proteolysis of HipB2 antitoxin by the Lon protease and the release of active HipA2 kinase, revealing a molecular mechanism that allows disparate stress conditions to be sensed and funneled into a single response pathway. The antitoxin is usually degraded by cellular proteases in response to various types of environmental signals [12] This posttranslational regulation enables the toxin to be released from the toxinantitoxin protein complex, resulting in cellular intoxication [10]. The hipA gene encodes a eukaryote-like serine-threonine kinase that phosphorylates tRNA-synthetase to inhibit protein translation [8, 9], while HipB antitoxin neutralizes HipA toxicity by forming a heterotetrameric protein complex, which is capable of binding to the promoter region of HipBA module to repress its transcription [15]

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