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

Abstract

<jats:title>Abstract</jats:title><jats:p>Bacteria have evolved diverse immunity mechanisms to protect themselves against the constant onslaught of bacteriophages<jats:sup>1–3</jats:sup>. Similar to how eukaryotic innate immune systems sense foreign invaders through pathogen-associated molecular patterns<jats:sup>4</jats:sup> (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 CapRel<jats:sup>SJ46</jats:sup>, a fused toxin–antitoxin system that protects <jats:italic>Escherichia coli</jats:italic> against diverse phages. Using genetic, biochemical and structural analyses, we demonstrate that the C-terminal domain of CapRel<jats:sup>SJ46</jats:sup> 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 CapRel<jats:sup>SJ46</jats:sup> 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’<jats:sup>5</jats:sup>, 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 hosts<jats:sup>6–10</jats:sup>, our results reveal a deeply conserved facet of immunity.</jats:p>