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A molecular link between cell wall biosynthesis, translation fidelity, and stringent response in Streptococcus pneumoniae
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Aggarwal, Surya D. , Lloyd, Adrian J., Yerneni, Saigopalakrishna S., Narciso, Ana Rita, Shepherd, Jennifer, Roper, David I., Dowson, Christopher G., Filipe, Sergio R and Hiller, N Luisa (2021) A molecular link between cell wall biosynthesis, translation fidelity, and stringent response in Streptococcus pneumoniae. Proceedings of the National Academy of Sciences of the United States of America, 118 (14). e2018089118. doi:10.1073/pnas.2018089118
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WRAP-molecular-link-between-cell-wall-biosynthesis-translation-fidelity-stringent-response-Streptococcus-pneumoniae-Lloyd-2021.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution Non-commercial No Derivatives 4.0. Download (1505Kb) | Preview |
Official URL: https://doi.org/10.1073/pnas.2018089118
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
| Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||
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| Subjects: | Q Science > QR Microbiology | ||||||||||||||||||||||||||||||||||||
| Divisions: | Faculty of Science > Life Sciences (2010- ) | ||||||||||||||||||||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Streptococcus pneumoniae , Streptococcus pneumoniae -- Effect of drugs on , Bacterial cell walls, Bacterial cell walls -- Synthesis | ||||||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Proceedings of the National Academy of Sciences of the United States of America | ||||||||||||||||||||||||||||||||||||
| Publisher: | National Academy of Sciences | ||||||||||||||||||||||||||||||||||||
| ISSN: | 0027-8424 | ||||||||||||||||||||||||||||||||||||
| Official Date: | 6 April 2021 | ||||||||||||||||||||||||||||||||||||
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| Volume: | 118 | ||||||||||||||||||||||||||||||||||||
| Number: | 14 | ||||||||||||||||||||||||||||||||||||
| Article Number: | e2018089118 | ||||||||||||||||||||||||||||||||||||
| DOI: | 10.1073/pnas.2018089118 | ||||||||||||||||||||||||||||||||||||
| Status: | Peer Reviewed | ||||||||||||||||||||||||||||||||||||
| Publication Status: | Published | ||||||||||||||||||||||||||||||||||||
| Access rights to Published version: | Open Access | ||||||||||||||||||||||||||||||||||||
| Copyright Holders: | National Academy of Sciences (USA) | ||||||||||||||||||||||||||||||||||||
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