Abstract
Toxin-antitoxin (TA) modules consist of a pair of genes that encode two components: a protein toxin and an antitoxin, which may be in the form of either a labile protein or an antisense small RNA. Here we describe, to the best of our knowledge, the first functional chromosomal type I TA system in streptococci. Our model organism is the oral pathogen Streptococcus mutans. Our results showed that the genome of S. mutans UA159 reference strain harbors a previously unannotated Fst-like toxin (Fst-Sm) and its cis-encoded small RNA antitoxin (srSm) converging towards the end of the toxin gene in IGR176, a small intergenic region of 318 nt. Fst-Sm is a small hydrophobic peptide of 32 amino acid residues with homology to the Fst toxin family. Transcripts of ∼200 nt and ∼70 nt specific to fst-Sm mRNA and srSm RNA, respectively, were detected by Northern blot analysis throughout S. mutans growth. The toxin mRNA was considerably more stable than its cognate antitoxin. The half-life of srSm RNA was determined to be ∼30 min, while fst-Sm mRNA had a half-life of ∼90 min. Both fst-Sm and srSm RNAs were transcribed across direct tandem repeats providing a region of complementarity for inhibition of toxin translation. Overproduction of Fst-Sm had a toxic effect on E. coli and S. mutans cells which can be neutralized by coexpression of srSm RNA. Deletion of fst-Sm/srSm locus or overexpression of Fst-Sm/srSm had no effect on S. mutans cell growth in liquid medium and no differences in the total biofilm biomass were noted. In contrast, mild-overproduction of Fst-Sm/srSm type I TA system decreases the levels of persister cells tolerant to bacterial cell wall synthesis inhibitors.
Highlights
Prokaryotic chromosomes contain small genetic elements encoding two components: a stable toxin and its less stable cognate antitoxin
While type II TAs are highly represented in bacterial chromosomes, little is known about the distribution of type I TA loci
The development of computational approaches to identify novel type I TA systems is challenging owing to the short, hydrophobic character of the toxins, and the difficulty in predicting the antitoxin small RNAs [4]
Summary
Prokaryotic chromosomes contain small genetic elements encoding two components: a stable toxin and its less stable cognate antitoxin. These modules are called toxin-antitoxin (TA) systems [1]. TA pairs form a stabilized complex in the cell preventing toxicity under normal growth conditions. Protein antitoxins neutralize the toxicity of the cognate toxin by forming a stable complex (type II) [8,9,10], by functioning as antagonists for the toxin activity (type IV) [11,12], or by inhibiting the toxin by cleaving its mRNA (type V) [13]. In E. coli, multiple type II TA systems have been linked to the formation of persister cells [18,19]
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