Dataset Information

Functionality and cross-regulation of the four SprG/SprF type I toxin-antitoxin systems in Staphylococcus aureus.

ABSTRACT: Toxin-antitoxin (TA) systems are ubiquitous among bacteria, frequently expressed in multiple copies, and important for functions such as antibiotic resistance and persistence. Type I TA systems are composed of a stable toxic peptide whose expression is repressed by an unstable RNA antitoxin. Here, we investigated the functionalities, regulation, and possible cross-talk between three core genome copies of the pathogenicity island-encoded 'sprG1/sprF1' type I TA system in the human pathogen Staphylococcus aureus. Except for SprG4, all RNA from these pairs, sprG2/sprF2, sprG3/sprF3, sprG4/sprF4, are expressed in the HG003 strain. SprG2 and SprG3 RNAs encode toxic peptides whose overexpression triggers bacteriostasis, which is counteracted at the RNA level by the overexpression of SprF2 and SprF3 antitoxins. Complex formation between each toxin and its cognate antitoxin involves their overlapping 3' ends, and each SprF antitoxin specifically neutralizes the toxicity of its cognate SprG toxin without cross-talk. However, overexpression studies suggest cross-regulations occur at the RNA level between the SprG/SprF TA systems during growth. When subjected to H2O2-induced oxidative stress, almost all antitoxin levels dropped, while only SprG1 and SprF1 were reduced during phagocytosis-induced oxidative stress. SprG1, SprF1, SprF2, SprG3 and SprF3 levels also decrease during hyperosmotic stress. This suggests that novel SprG/SprF TA systems are involved in S. aureus persistence.

SUBMITTER: Riffaud C

PROVIDER: S-EPMC6393307 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Functionality and cross-regulation of the four SprG/SprF type I toxin-antitoxin systems in Staphylococcus aureus.

Riffaud Camille C Pinel-Marie Marie-Laure ML Pascreau Gaëtan G Felden Brice B

Nucleic acids research 20190201 4

Toxin-antitoxin (TA) systems are ubiquitous among bacteria, frequently expressed in multiple copies, and important for functions such as antibiotic resistance and persistence. Type I TA systems are composed of a stable toxic peptide whose expression is repressed by an unstable RNA antitoxin. Here, we investigated the functionalities, regulation, and possible cross-talk between three core genome copies of the pathogenicity island-encoded 'sprG1/sprF1' type I TA system in the human pathogen Staphy ...[more]

PMID: 30551143

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Project description:Toxin-antitoxin (TA) systems consist of toxin-inhibiting diverse cellular functions (e.g., DNA replication, transcription, and translation) and a noncoding RNA or protein antitoxin. TA systems are associated with various cellular events, such as stress responses, programmed cell death, and bacterial pathogenicity. Recent advances in genome sequencing and bioinformatics research have demonstrated that most bacteria harbor various kinds of TA modules on their chromosomes; however, there is little understanding of chromosomally encoded TA systems in the Gram-positive pathogen Staphylococcus aureus Here, we report on newly discovered S. aureus TA systems, each of which is composed of two proteins. Manual search and gene operon prediction analysis identified eight 2-gene operons as potential candidates for TA systems. Subsequently, using an Escherichia coli host killing and rescue assay, we demonstrated that four of the eight candidates worked as TA systems, designated tsaAT, tsbAT, tscAT, and tsdAT Moreover, the TsaT, TsbT, TscT, and TsdT toxins inhibited S. aureus growth, and the toxicity of TsbT was neutralized by coexpressing the tsbA gene in the native host, S. aureus Further, the bioinformatics analysis of the gene clusters revealed that TsaAT, TsbAT, TscAT, and TsdAT did not exhibit sequence similarity to known bacterial TA systems, and their homologues were present only within Staphylococcus species and not among any other bacteria. Our results further advance not only the understanding of S. aureus TA systems but also the study of unannotated TA systems in various bacterial species.IMPORTANCE Recent advances in genome sequencing and bioinformatics research have demonstrated that most pathogenic bacteria harbor a large number of chromosomally encoded toxin-antitoxin (TA) modules. However, little is known about the TA systems in S. aureus Here, we newly identified four S. aureus TA systems using a combination of manual base-by-base screening and functional analysis in E. coli Moreover, all toxins of the identified TA systems caused growth inhibition in the native host S. aureus Although the newly identified TA systems did not exhibit sequence similarity with known bacterial TA systems, their orthologues were conserved only among other Staphylococcus species, indicating their uniqueness to staphylococci. Our approach opens the possibility for studying unannotated TA systems in various bacterial species.

Project description:Bacterial cells respond to environmental stresses by modulating their gene expression and adjusting their proteome. In Staphylococcus aureus, selective degradation by ClpP protease eliminates damaged proteins and regulates the abundance of functional proteins such as many important stress-induced transcriptional regulators. Degradation by ClpP requires the unfolding activity of partner Clp ATPases, such as ClpX and ClpC, and assistance of substrate-specific adaptor proteins such as YjbH and TrfA. Herein, we demonstrated that YjbH is aggregated in response to growth stress stimuli, such as oxidative and antibiotic stresses. In consequence, its function as an adaptor protein is compromised. YjbH controls the degradation of the stress-induced transcriptional regulator, Spx. Aggregated YjbH cannot assist Spx degradation, which results in Spx accumulation. We discovered that depending on the stress stimulus, Spx can be soluble or insoluble, and, consequently, transcriptionally active or inactive. Therefore, Spx accumulation and solubility are key components governing activation of Spx-dependent genes. Spx positively regulates expression of a ClpCP adaptor protein TrfA. TrfA in turn is required for degradation of MazE antitoxin, the unstable component of the MazEF toxin-antitoxin system, that neutralizes the endoribonuclease activity of MazF toxin. Bacterial toxin-antitoxin systems are associated with dormancy and tolerance to antibiotics that are related to chronic and relapsing infections, and it is at present a key unresolved problem in medicine. MazF activity was linked to growth stasis, yet the precise environmental signals that trigger MazE degradation and MazF activation are poorly understood. Here we propose a model where YjbH serves as a sensor of environmental stresses for downstream regulation of MazEF activity. YjbH aggregation, soluble Spx, and TrfA, coordinately control MazE antitoxin levels and consequently MazF toxin activity. This model implies that certain stress conditions culminate in modulation of MazF activity resulting in growth stasis during in vivo infections.

Dataset Information

Functionality and cross-regulation of the four SprG/SprF type I toxin-antitoxin systems in Staphylococcus aureus.

Publications

Functionality and cross-regulation of the four SprG/SprF type I toxin-antitoxin systems in Staphylococcus aureus.

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