Direct activation of a bacterial innate immune system by a viral capsid protein

Tong Zhang, Hedvig Tamman, Kyo Coppieters ’t Wallant, Tatsuaki Kurata, Michele LeRoux, Sriram Srikant, Tetiana Brodiazhenko, Albinas Cepauskas, Ariel Talavera, Chloe Martens, Gemma C. Atkinson, Vasili Hauryliuk (), Abel Garcia-Pino () and Michael T. Laub ()
Additional contact information
Tong Zhang: Massachusetts Institute of Technology
Hedvig Tamman: Université Libre de Bruxelles, (ULB)
Kyo Coppieters ’t Wallant: Université Libre de Bruxelles (ULB)
Tatsuaki Kurata: Lund University
Michele LeRoux: Massachusetts Institute of Technology
Sriram Srikant: Massachusetts Institute of Technology
Tetiana Brodiazhenko: University of Tartu
Albinas Cepauskas: Université Libre de Bruxelles, (ULB)
Ariel Talavera: Université Libre de Bruxelles, (ULB)
Chloe Martens: Université Libre de Bruxelles (ULB)
Gemma C. Atkinson: Lund University
Vasili Hauryliuk: Lund University
Abel Garcia-Pino: Université Libre de Bruxelles, (ULB)
Michael T. Laub: Massachusetts Institute of Technology

Nature, 2022, vol. 612, issue 7938, 132-140

Abstract: Abstract Bacteria have evolved diverse immunity mechanisms to protect themselves against the constant onslaught of bacteriophages1–3. Similar to how eukaryotic innate immune systems sense foreign invaders through pathogen-associated molecular patterns4 (PAMPs), many bacterial immune systems that respond to bacteriophage infection require phage-specific triggers to be activated. However, the identities of such triggers and the sensing mechanisms remain largely unknown. Here we identify and investigate the anti-phage function of CapRelSJ46, a fused toxin–antitoxin system that protects Escherichia coli against diverse phages. Using genetic, biochemical and structural analyses, we demonstrate that the C-terminal domain of CapRelSJ46 regulates the toxic N-terminal region, serving as both antitoxin and phage infection sensor. Following infection by certain phages, newly synthesized major capsid protein binds directly to the C-terminal domain of CapRelSJ46 to relieve autoinhibition, enabling the toxin domain to pyrophosphorylate tRNAs, which blocks translation to restrict viral infection. Collectively, our results reveal the molecular mechanism by which a bacterial immune system directly senses a conserved, essential component of phages, suggesting a PAMP-like sensing model for toxin–antitoxin-mediated innate immunity in bacteria. We provide evidence that CapRels and their phage-encoded triggers are engaged in a ‘Red Queen conflict’5, revealing a new front in the intense coevolutionary battle between phages and bacteria. Given that capsid proteins of some eukaryotic viruses are known to stimulate innate immune signalling in mammalian hosts6–10, our results reveal a deeply conserved facet of immunity.

Date: 2022
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DOI: 10.1038/s41586-022-05444-z

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