An old fold can learn new tricks
Toxin-antitoxin (TA) systems, discovered decades ago, are small operons encoding a toxic protein and an antitoxin protein inhibiting the toxin activity by forming a tight complex. TA systems are widespread and abundant in bacterial genomes and might represent up to 3% of the total predicted open reading frames (ORFs) in some genomes, with some genomes containing more than 90 TA systems. Originally viewed as self-destructive ticking bombs of the bacterial chromosome TA modules have captivated microbiologists for their promise in applied research. However despite their ubiquitous distribution and years of active research, their functions remain controversial.
RelA-SpoT Homolog (RSH) enzymes control bacterial physiology through synthesis and degradation of the nucleotide alarmone (p)ppGpp. Through a collaborative effort between the groups of Abel Garcia-Pino (Welbio Investigator at the ULB) and Vasili Hauryliuk and Gemma C. Atkinson (University of Lund), the team recently discovered multiple families of small RSH enzymes acting as toxins of toxin-antitoxin (TA) modules, and is now proposing a novel mechanism of growth arrest used by four experimentally unexplored subfamilies.
Surprisingly, all these toxins, that likely evolved from an ancestral long RSH gene, specifically inhibit protein synthesis. To do so, they pyrophosphorylate the amino-acceptor end of uncharged tRNAs. The modification inhibits both tRNA aminoacylation and the sensing of cellular amino acid starvation by the ribosome-associated RSH RelA. The remarkable evolution of some of these TA modules seems to recreate the opposing activities of the housekeeping long RSH enzymes since a small alarmone hysdrolase that is part of the operon can reverse the pyrophosphorylation of tRNA to counter the growth inhibition. The position of the families with this activity at roughly the midpoint of the RSH raises the possibility of an ancestral function of this fold at a time predating the last universal common ancestor (LUCA) that could have been pyrophosphorylation of RNA, rather than synthesis of nucleotide alarmones.
Reference : Kurata et al. (2021) Mol Cell 81 : 3160-317 DOI: 10.1016/j.molcel.2021.06.005
Source : Abel Garcia-Pino