A molecular link between cell wall biosynthesis, translation fidelity, and stringent response in Streptococcus pneumoniae

Surya D. Aggarwal, Adrian J. Lloyd, Saigopalakrishna S. Yerneni, Ana Rita Narciso, Jennifer Shepherd, David I. Roper, Christopher G. Dowson, Sergio R. Filipe, N. Luisa Hiller

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Abstract

Survival in the human host requires bacteria to respond to unfavorable conditions. In the important Gram-positive pathogen Streptococcus pneumoniae, cell wall biosynthesis proteins MurM and MurN are tRNA-dependent amino acyl transferases which lead to the production of branched muropeptides. We demonstrate that wild-type cells experience optimal growth under mildly acidic stressed conditions, but ΔmurMN strain displays growth arrest and extensive lysis. Furthermore, these stress conditions compromise the efficiency with which alanyl-tRNAAla synthetase can avoid noncognate mischarging of tRNAAla with serine, which is toxic to cells. The observed growth defects are rescued by inhibition of the stringent response pathway or by overexpression of the editing domain of alanyl-tRNAAla synthetase that enables detoxification of tRNA misacylation. Furthermore, MurM can incorporate seryl groups from mischarged Seryl-tRNAAlaUGC into cell wall precursors with exquisite specificity. We conclude that MurM contributes to the fidelity of translation control and modulates the stress response by decreasing the pool of mischarged tRNAs. Finally, we show that enhanced lysis of ΔmurMN pneumococci is caused by LytA, and the murMN operon influences macrophage phagocytosis in a LytA-dependent manner. Thus, MurMN attenuates stress responses with consequences for host-pathogen interactions. Our data suggest a causal link between misaminoacylated tRNA accumulation and activation of the stringent response. In order to prevent potential corruption of translation, consumption of seryl-tRNAAla by MurM may represent a first line of defense. When this mechanism is overwhelmed or absent (ΔmurMN), the stringent response shuts down translation to avoid toxic generation of mistranslated/misfolded proteins.

Original languageEnglish
Article numbere2018089118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number14
DOIs
Publication statusPublished - 6 Apr 2021

Keywords

  • autolysis
  • cell wall
  • Streptococcus pneumoniae
  • stringent response
  • translation quality control

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