%0 Generic
%A Bomponis, Iakovos
%C Heidelberg
%D 2022
%F heidok:31572
%R 10.11588/heidok.00031572
%T Bacterial retrons encode phage-sensing  toxin/antitoxin systems
%U https://archiv.ub.uni-heidelberg.de/volltextserver/31572/
%X Retrons are prokaryotic genetic systems containing reverse transcriptases (RTs) that  produce multiple copies of small single-stranded DNA (msDNA). Despite our  understanding of the complex msDNA biosynthesis, the physiological role of retrons  has remained elusive. I established that the Retron-Sen2 in Salmonella Typhimurium  (STm) encodes a toxin, which I have named RcaT (Retron cold-anaerobic Toxin).  RcaT is activated when msDNA biosynthesis is perturbed and inhibits STm growth at  ambient temperatures or during anaerobiosis. The RT and msDNA are both necessary  to counteract RcaT, by forming an RT-msDNA complex that inactivates RcaT through  direct protein-protein interactions. Thus, retrons constitute a novel family of tripartite  toxin/antitoxin systems (TAs), where the RcaT toxin is inactivated by the RT-msDNA  antitoxin.  Bacteria carry dozens of TAs in their chromosomes. Normally, the antitoxin is coexpressed  and neutralizes its cognate toxin, but TAs can be activated to inhibit  bacterial growth. Yet, when and how TAs are triggered remains an enigma, hindering  our understanding of their physiological roles. I developed TIC/TAC (Toxin  Inhibition/Activation Conjugation), a high-throughput reverse genetics approach, to  systematically identify molecular blockers and triggers of TAs. By applying TIC/TAC  to Retron-Sen2, I identified multiple blockers and triggers of phage origin. Diverse  phage proteins trigger RcaT toxicity by directly interacting with the msDNA-part of the  antitoxin. Phage proteins can circumvent activation by directly blocking the activity of  RcaT. I propose that retron-TAs act as abortive-infection anti-phage defense systems  and delineate the mechanistic principles behind the retron-phage arms-race.