Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 14, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2018089118
Keywords
Streptococcus pneumoniae; cell wall; translation quality control; stringent response; autolysis
Categories
Funding
- NIH [R00-DC-011322]
- Glen de Vries Presidential Fellowship
- Eberly Family Trust
- Department of Biological Sciences at Carnegie Mellon University
- Portuguese national funds [PTDC/BIA-MIC/30746/2017]
- UCIBIO research unit [UID/Multi/04378/2019]
- ONEIDA (an omics network to prevent and control infectious diseases and antimicrobial resistance) project [LISBOA-01-0145-FEDER-016417]
- Medical Research Council [G0400848, G1100127, MR/N002679/1]
- Stupakoff Scientific Achievement Award
- Fundação para a Ciência e a Tecnologia [UID/Multi/04378/2019, PTDC/BIA-MIC/30746/2017] Funding Source: FCT
- MRC [MR/N002679/1, G0400848, G1100127] Funding Source: UKRI
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In response to unfavorable conditions, the Gram-positive pathogen Streptococcus pneumoniae relies on cell wall biosynthesis proteins MurM and MurN. MurM modulates stress response by decreasing the pool of mischarged tRNAs, while enhanced lysis in the absence of MurM may be caused by LytA.
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 Delta murMN strain displays growth arrest and extensive lysis. Furthermore, these stress conditions compromise the efficiency with which alanyl-tRNA(Ala) synthetase can avoid noncognate mischarging of tRNA(Ala) 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-tRNA(Ala) synthetase that enables detoxification of tRNA misacylation. Furthermore, MurM can incorporate seryl groups from mischarged Seryl-tRNA(UGC)(Ala) 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 Delta murMN 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-tRNA(Ala) by MurM may represent a first line of defense. When this mechanism is overwhelmed or absent (Delta murMN), the stringent response shuts down translation to avoid toxic generation of mistranslated/misfolded proteins.
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