The Fst/Ldr Family of Type I TA System Toxins: Potential Roles in Stress Response, Metabolism and Pathogenesis

Abstract

The parpAD1 locus was the first type I toxin–antitoxin (TA) system described in Gram-positive bacteria and was later determined to be the founding member of a widely distributed family of plasmid- and chromosomally encoded TA systems. Indeed, homology searches revealed that the toxin component, FstpAD1, is a member of the Fst/Ldr superfamily of peptide toxins found in both Gram-positive and Gram-negative bacteria. Regulation of the Fst and Ldr toxins is distinct in their respective Gram-positive and Gram-negative hosts, but the effects of ectopic over-expression are similar. While, the plasmid versions of these systems appear to play the canonical role of post-segregational killing stability mechanisms, the function of the chromosomal systems remains largely obscure. At least one member of the family has been suggested to play a role in pathogenesis in Staphylococcus aureus, while the regulation of several others appear to be tightly integrated with genes involved in sugar metabolism. After a brief discussion of the regulation and function of the foundational parpAD1 locus, this review will focus on the current information available on potential roles of the chromosomal homologs.

RNA Regulated Toxin-Antitoxin Systems in Pathogenic Bacteria

“…Rather than disrupting the membrane potential, the BsrG toxin of B. subtilis and the AapA1 toxin of Helicobacter pylori target cell envelope synthesis directly, resulting in the formation of invaginations within the cell and ultimately cell lysis ( Jahn et al., 2015 ; El Mortaji et al., 2020 ). Other Type I TA system toxins mediate their lethal effect via endoribonuclease activity ( Kawano, 2012 ), endodeoxyribonuclease activity ( Guo et al., 2014 ) or by promoting nucleoid condensation ( Weaver, 2020 ). These toxic activities are exemplified by the toxin component of the E. coli SymE-SymR TA system, the E. coli RalR-RalA TA system, and the Enterococcus faecalis Fst-RNAII TA system, respectively ( Kawano, 2012 ; Guo et al., 2014 ; Weaver, 2020 ).…”

“…Other Type I TA system toxins mediate their lethal effect via endoribonuclease activity ( Kawano, 2012 ), endodeoxyribonuclease activity ( Guo et al., 2014 ) or by promoting nucleoid condensation ( Weaver, 2020 ). These toxic activities are exemplified by the toxin component of the E. coli SymE-SymR TA system, the E. coli RalR-RalA TA system, and the Enterococcus faecalis Fst-RNAII TA system, respectively ( Kawano, 2012 ; Guo et al., 2014 ; Weaver, 2020 ). The activity, target(s) and function of select Type I and Type III toxin is summarized in Table 1 .…”

Charged Residues Flanking the Transmembrane Domain of Two Related Toxin–Antitoxin System Toxins Affect Host Response

“…The toxins of type I TA systems (TA-1) are generally small proteins of less than 50 amino acids, whose translation is repressed by a small regulatory RNA [ 10 , 11 ]. These proteins contain a stretch of hydrophobic residues forming a putative transmembrane (TM) domain and some have been demonstrated to be membrane localized [ 12 , 13 ]. Originally identified as plasmid stability loci operating via a PSK mechanism, it was presumed that they functioned by forming non-specific pores and disrupting membrane function [ 4 ].…”

Toxin–Antitoxin Systems in Pathogenic Bacteria

“…A review paper provides a good overview of how the widespread family of membrane active peptides, Fst/Ldr, is regulated by small RNAs in the TA type I system [7]. Weaver's review shows that the regulation of the Fst and Ldr toxins is distinct in their respective Gram-positive and Gram-negative hosts, but the effects of ectopic over-expression are similar.…”

“…Weaver's review shows that the regulation of the Fst and Ldr toxins is distinct in their respective Gram-positive and Gram-negative hosts, but the effects of ectopic over-expression are similar. Limited toxin expression could conceivably function to slow bacterial growth and halt cell proliferation, playing its canonical role in plasmid stabilization [7].…”