Direct activation of a bacterial innate immune system by a viral capsid protein
(2022) In Nature 612(7938). p.132-140- 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... (More)
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.
(Less)
- author
- Zhang, Tong
; Tamman, Hedvig
; Coppieters 't Wallant, Kyo
; Kurata, Tatsuaki
LU
; LeRoux, Michele
; Srikant, Sriram
; Brodiazhenko, Tetiana
; Cepauskas, Albinas
; Talavera, Ariel
; Martens, Chloe
; Atkinson, Gemma C
LU
; Hauryliuk, Vasili
LU
; Garcia-Pino, Abel
and Laub, Michael T
LU
(Less) - organization
- publishing date
- 2022-12-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Bacteriology, Bacteriophages
- in
- Nature
- volume
- 612
- issue
- 7938
- pages
- 9 pages
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:36385533
- scopus:85141941741
- ISSN
- 0028-0836
- DOI
- 10.1038/s41586-022-05444-z
- language
- English
- LU publication?
- yes
- additional info
- © 2022. The Author(s).
- id
- bf4c0106-59fa-4939-99c3-8b72f6d7c4d1
- date added to LUP
- 2022-11-21 16:26:02
- date last changed
- 2024-06-12 03:59:24
@article{bf4c0106-59fa-4939-99c3-8b72f6d7c4d1,
abstract = {{<p>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.</p>}},
author = {{Zhang, Tong and Tamman, Hedvig and Coppieters 't Wallant, Kyo and Kurata, Tatsuaki and LeRoux, Michele and Srikant, Sriram and Brodiazhenko, Tetiana and Cepauskas, Albinas and Talavera, Ariel and Martens, Chloe and Atkinson, Gemma C and Hauryliuk, Vasili and Garcia-Pino, Abel and Laub, Michael T}},
issn = {{0028-0836}},
keywords = {{Bacteriology; Bacteriophages}},
language = {{eng}},
month = {{12}},
number = {{7938}},
pages = {{132--140}},
publisher = {{Nature Publishing Group}},
series = {{Nature}},
title = {{Direct activation of a bacterial innate immune system by a viral capsid protein}},
url = {{http://dx.doi.org/10.1038/s41586-022-05444-z}},
doi = {{10.1038/s41586-022-05444-z}},
volume = {{612}},
year = {{2022}},
}