TY - JOUR
T1 - Mechanism of phage sensing and restriction by toxin-antitoxin-chaperone systems
AU - Mets, Toomas
AU - Kurata, Tatsuaki
AU - Ernits, Karin
AU - Johansson, Marcus J O
AU - Craig, Sophie Z
AU - Evora, Gabriel Medina
AU - Buttress, Jessica A
AU - Odai, Roni
AU - Wallant, Kyo Coppieters't
AU - Nakamoto, Jose A
AU - Shyrokova, Lena
AU - Egorov, Artyom A
AU - Doering, Christopher Ross
AU - Brodiazhenko, Tetiana
AU - Laub, Michael T
AU - Tenson, Tanel
AU - Strahl, Henrik
AU - Martens, Chloe
AU - Harms, Alexander
AU - Garcia-Pino, Abel
AU - Atkinson, Gemma C
AU - Hauryliuk, Vasili
PY - 2024
Y1 - 2024
N2 - Toxin-antitoxins (TAs) are prokaryotic two-gene systems composed of a toxin neutralized by an antitoxin. Toxin-antitoxin-chaperone (TAC) systems additionally include a SecB-like chaperone that stabilizes the antitoxin by recognizing its chaperone addiction (ChAD) element. TACs mediate antiphage defense, but the mechanisms of viral sensing and restriction are unexplored. We identify two Escherichia coli antiphage TAC systems containing host inhibition of growth (HigBA) and CmdTA TA modules, HigBAC and CmdTAC. HigBAC is triggered through recognition of the gpV major tail protein of phage λ. Chaperone HigC recognizes gpV and ChAD via analogous aromatic molecular patterns, with gpV outcompeting ChAD to trigger toxicity. For CmdTAC, the CmdT ADP-ribosyltransferase toxin modifies mRNA to halt protein synthesis and limit phage propagation. Finally, we establish the modularity of TACs by creating a hybrid broad-spectrum antiphage system combining the CmdTA TA warhead with a HigC chaperone phage sensor. Collectively, these findings reveal the potential of TAC systems in broad-spectrum antiphage defense.
AB - Toxin-antitoxins (TAs) are prokaryotic two-gene systems composed of a toxin neutralized by an antitoxin. Toxin-antitoxin-chaperone (TAC) systems additionally include a SecB-like chaperone that stabilizes the antitoxin by recognizing its chaperone addiction (ChAD) element. TACs mediate antiphage defense, but the mechanisms of viral sensing and restriction are unexplored. We identify two Escherichia coli antiphage TAC systems containing host inhibition of growth (HigBA) and CmdTA TA modules, HigBAC and CmdTAC. HigBAC is triggered through recognition of the gpV major tail protein of phage λ. Chaperone HigC recognizes gpV and ChAD via analogous aromatic molecular patterns, with gpV outcompeting ChAD to trigger toxicity. For CmdTAC, the CmdT ADP-ribosyltransferase toxin modifies mRNA to halt protein synthesis and limit phage propagation. Finally, we establish the modularity of TACs by creating a hybrid broad-spectrum antiphage system combining the CmdTA TA warhead with a HigC chaperone phage sensor. Collectively, these findings reveal the potential of TAC systems in broad-spectrum antiphage defense.
U2 - 10.1016/j.chom.2024.05.003
DO - 10.1016/j.chom.2024.05.003
M3 - Article
C2 - 38821063
SN - 1934-6069
VL - 32
SP - 1059-1073.e8
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 7
ER -