Mechanism of phage sensing and restriction by toxin-antitoxin-chaperone systems.

Chloe Martens, Alexander Harms, Christopher Ross Doering, Lena Shyrokova, Kyo Coppieters't Wallant, Roni Odai, Gabriel Medina Evora, Marcus J O Johansson, Artyom A Egorov, Abel Garcia-Pino, Vasili Hauryliuk, Jessica A Buttress, Sophie Z Craig, Karin Ernits, Gemma C Atkinson, Tatsuaki Kurata, Jose A Nakamoto, Tetiana Brodiazhenko, Toomas Mets, Tanel Tenson, Henrik Strahl, Michael T Laub

Journal: Cell host & microbe 2024;32(7):1059-1073.e8

PMID: 38821063

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Abstract

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.

Address: Department of Experimental Medical Science, Lund University, 221 00 Lund, Sweden; University of Tartu, Institute of Technology, 50411 Tartu, Estonia.; Department of Experimental Medical Science, Lund University, 221 00 Lund, Sweden.; Cellular and Molecular Microbiology (CM2), Faculté des Sciences, Université Libre de Bruxelles (ULB), Campus La Plaine, Building BC, Room 1C4203, Boulevard du Triomphe, 1050 Brussels, Belgium.; Department of Experimental Medical Science, Lund University, 221 00 Lund, Sweden; Cellular and Molecular Microbiology (CM2), Faculté des Sciences, Université Libre de Bruxelles (ULB), Campus La Plaine, Building BC, Room 1C4203, Boulevard du Triomphe, 1050 Brussels, Belgium.; Centre for Bacterial Cell Biology, Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4AX, UK.; Centre for Structural Biology and Bioinformatics, Université Libre de Bruxelles (ULB), Boulevard du Triomphe, Building BC, 1050 Bruxelles, Belgium.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.; University of Tartu, Institute of Technology, 50411 Tartu, Estonia.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA.; ETH Zurich, Institute of Food, Nutrition and Health, 8092 Zürich, Switzerland.; Cellular and Molecular Microbiology (CM2), Faculté des Sciences, Université Libre de Bruxelles (ULB), Campus La Plaine, Building BC, Room 1C4203, Boulevard du Triomphe, 1050 Brussels, Belgium. Electronic address: [email protected].; Department of Experimental Medical Science, Lund University, 221 00 Lund, Sweden; Virus Centre, Lund University, Lund, Sweden. Electronic address: [email protected].; Department of Experimental Medical Science, Lund University, 221 00 Lund, Sweden; University of Tartu, Institute of Technology, 50411 Tartu, Estonia; Virus Centre, Lund University, Lund, Sweden; Science for Life Laboratory, Lund, Sweden. Electronic address: [email protected].

DOI: 10.1016/j.chom.2024.05.003

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MeSH Terms: Toxin-Antitoxin Systems, Molecular Chaperones, Escherichia coli, Escherichia coli Proteins, Bacteriophage lambda, Bacterial Toxins, Bacteriophages, Antitoxins, Viral Tail Proteins