RNA Regulated Toxin-Antitoxin Systems in Pathogenic Bacteria

Sarpong, David D.; Murphy, Erin R.

doi:10.3389/fcimb.2021.661026

Cited by 9 publications

(5 citation statements)

References 132 publications

(302 reference statements)

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“…Antisense RNAs are encoded on the opposite DNA strand and, consequently, regulate their cognate mRNA target via perfect base-pairings. They are notably involved in toxin-antitoxin systems ( Sarpong and Murphy, 2021 ). Riboswitches are regulatory elements embedded within the 5’ untranslated region (5’UTR) of mRNA targets ( Breaker, 2022 ).…”

Section: What Are Bacterial Regulatory Rnas?mentioning

confidence: 99%

Battle for Metals: Regulatory RNAs at the Front Line

Charbonnier

González-Espinoza

Kehl-Fie

et al. 2022

Front. Cell. Infect. Microbiol.

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Metal such as iron, zinc, manganese, and nickel are essential elements for bacteria. These nutrients are required in crucial structural and catalytic roles in biological processes, including precursor biosynthesis, DNA replication, transcription, respiration, and oxidative stress responses. While essential, in excess these nutrients can also be toxic. The immune system leverages both of these facets, to limit bacterial proliferation and combat invaders. Metal binding immune proteins reduce the bioavailability of metals at the infection sites starving intruders, while immune cells intoxicate pathogens by providing metals in excess leading to enzyme mismetallation and/or reactive oxygen species generation. In this dynamic metal environment, maintaining metal homeostasis is a critical process that must be precisely coordinated. To achieve this, bacteria utilize diverse metal uptake and efflux systems controlled by metalloregulatory proteins. Recently, small regulatory RNAs (sRNAs) have been revealed to be critical post-transcriptional regulators, working in conjunction with transcription factors to promote rapid adaptation and to fine-tune bacterial adaptation to metal abundance. In this mini review, we discuss the expanding role for sRNAs in iron homeostasis, but also in orchestrating adaptation to the availability of other metals like manganese and nickel. Furthermore, we describe the sRNA-mediated interdependency between metal homeostasis and oxidative stress responses, and how regulatory networks controlled by sRNAs contribute to survival and virulence.

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Section: What Are Bacterial Regulatory Rnas?mentioning

confidence: 99%

Battle for Metals: Regulatory RNAs at the Front Line

Charbonnier

González-Espinoza

Kehl-Fie

et al. 2022

Front. Cell. Infect. Microbiol.

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“…TA systems are small genetic elements that are prevalent in most prokaryote genomes 1 – 3 . TA systems comprise two genes that encode for a stable toxin and unstable antitoxin 1 – 7 . TA systems have been classified into eight types based on the nature of antitoxin (protein or RNA) and the mechanisms by which toxin activity is neutralized 2 , 8 .…”

Section: Introductionmentioning

confidence: 99%

Mycobacterium tuberculosis strain with deletions in menT3 and menT4 is attenuated and confers protection in mice and guinea pigs

Gosain,

Chugh,

Rizvi

et al. 2024

Nat Commun

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The genome of Mycobacterium tuberculosis encodes for a large repertoire of toxin-antitoxin systems. In the present study, MenT3 and MenT4 toxins belonging to MenAT subfamily of TA systems have been functionally characterized. We demonstrate that ectopic expression of these toxins inhibits bacterial growth and this is rescued upon co-expression of their cognate antitoxins. Here, we show that simultaneous deletion of menT3 and menT4 results in enhanced susceptibility of M. tuberculosis upon exposure to oxidative stress and attenuated growth in guinea pigs and mice. We observed reduced expression of transcripts encoding for proteins that are essential or required for intracellular growth in mid-log phase cultures of ΔmenT4ΔT3 compared to parental strain. Further, the transcript levels of proteins involved in efficient bacterial clearance were increased in lung tissues of ΔmenT4ΔT3 infected mice relative to parental strain infected mice. We show that immunization of mice and guinea pigs with ΔmenT4ΔT3 confers significant protection against M. tuberculosis infection. Remarkably, immunization of mice with ΔmenT4ΔT3 results in increased antigen-specific TH1 bias and activated memory T cell response. We conclude that MenT3 and MenT4 are important for M. tuberculosis pathogenicity and strains lacking menT3 and menT4 have the potential to be explored further as vaccine candidates.

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“…While the regulation of the TisB toxin as it relates to function is well defined, this has not been the case for many other chromosomal type I systems ( 5 – 7 ). One reason for this is that attempts to identify novel regulatory mechanisms bioinformatically have had limited success.…”

Section: Introductionmentioning

confidence: 99%

A simple BLASTn-based approach generates novel insights into the regulation and biological function of type I toxin-antitoxins

Shore,

Ptacek,

Steen

et al. 2024

mSystems

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Bacterial chromosomal type I toxin-antitoxin systems consist of a small protein, typically under 60 amino acids, and a small RNA (sRNA) that represses toxin translation. These gene pairs have gained attention over the last decade for their contribution to antibiotic persistence and phage tolerance in bacteria. However, biological functions for many remain elusive as gene deletions often fail to produce an observable phenotype. For many pairs, it is still unknown when the toxin and/or antitoxin gene are natively expressed within the bacterium. We examined sequence conservation of three type I toxin-antitoxin systems, tisB/istR-1, shoB/ohsC, and zor/orz , in over 2,000 Escherichia coli strains, including pathogenic and commensal isolates. Using our custom database, we found that these gene pairs are widespread across E. coli and have expression potential via BLASTn. We identified an alternative, dominant sequence variant of TisB and confirmed that it is toxic upon overproduction. Additionally, analyses revealed a highly conserved sequence in the zorO mRNA untranslated region that is required for full toxicity. We further noted that over 30% of E. coli genomes contain an orz antitoxin gene only and confirmed its expression in a representative strain: the first confirmed report of a type I antitoxin without its cognate toxin. Our results add to our understanding of these systems, and our methodology is applicable for other type I loci to identify critical regulatory and functional features. IMPORTANCE Chromosomal type I toxin-antitoxins are a class of genes that have gained increasing attention over the last decade for their roles in antibiotic persistence which may contribute to therapeutic failures. However, the control of many of these genes and when they function have remained elusive. We demonstrate that a simple genetic conservation-based approach utilizing free, publicly available data yields known and novel insights into the regulation and function of three chromosomal type I toxin-antitoxins in Escherichia coli . This study also provides a framework for how this approach could be applied to other genes of interest.

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RNA Regulated Toxin-Antitoxin Systems in Pathogenic Bacteria

Cited by 9 publications

References 132 publications

Battle for Metals: Regulatory RNAs at the Front Line

Battle for Metals: Regulatory RNAs at the Front Line

Mycobacterium tuberculosis strain with deletions in menT3 and menT4 is attenuated and confers protection in mice and guinea pigs

A simple BLASTn-based approach generates novel insights into the regulation and biological function of type I toxin-antitoxins

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