Retron-Eco1 assembles NAD+-hydrolyzing filaments that provide immunity against bacteriophages
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
Retron-Eco1 assembles NAD+-hydrolyzing filaments that provide immunity against bacteriophages. / Carabias, Arturo; Camara-Wilpert, Sarah; Mestre, Mario Rodríguez; Lopéz-Méndez, Blanca; Hendriks, Ivo A.; Zhao, Ruiliang; Pape, Tillmann; Fuglsang, Anders; Luk, Sean Hoi Ching; Nielsen, Michael L.; Pinilla-Redondo, Rafael; Montoya, Guillermo.
I: Molecular Cell, Bind 84, Nr. 11, 2024, s. 2185-2202.e12.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Retron-Eco1 assembles NAD+-hydrolyzing filaments that provide immunity against bacteriophages
AU - Carabias, Arturo
AU - Camara-Wilpert, Sarah
AU - Mestre, Mario Rodríguez
AU - Lopéz-Méndez, Blanca
AU - Hendriks, Ivo A.
AU - Zhao, Ruiliang
AU - Pape, Tillmann
AU - Fuglsang, Anders
AU - Luk, Sean Hoi Ching
AU - Nielsen, Michael L.
AU - Pinilla-Redondo, Rafael
AU - Montoya, Guillermo
N1 - Publisher Copyright: © 2024 Elsevier Inc.
PY - 2024
Y1 - 2024
N2 - Retrons are toxin-antitoxin systems protecting bacteria against bacteriophages via abortive infection. The Retron-Eco1 antitoxin is formed by a reverse transcriptase (RT) and a non-coding RNA (ncRNA)/multi-copy single-stranded DNA (msDNA) hybrid that neutralizes an uncharacterized toxic effector. Yet, the molecular mechanisms underlying phage defense remain unknown. Here, we show that the N-glycosidase effector, which belongs to the STIR superfamily, hydrolyzes NAD+ during infection. Cryoelectron microscopy (cryo-EM) analysis shows that the msDNA stabilizes a filament that cages the effector in a low-activity state in which ADPr, a NAD+ hydrolysis product, is covalently linked to the catalytic E106 residue. Mutations shortening the msDNA induce filament disassembly and the effector's toxicity, underscoring the msDNA role in immunity. Furthermore, we discovered a phage-encoded Retron-Eco1 inhibitor (U56) that binds ADPr, highlighting the intricate interplay between retron systems and phage evolution. Our work outlines the structural basis of Retron-Eco1 defense, uncovering ADPr's pivotal role in immunity.
AB - Retrons are toxin-antitoxin systems protecting bacteria against bacteriophages via abortive infection. The Retron-Eco1 antitoxin is formed by a reverse transcriptase (RT) and a non-coding RNA (ncRNA)/multi-copy single-stranded DNA (msDNA) hybrid that neutralizes an uncharacterized toxic effector. Yet, the molecular mechanisms underlying phage defense remain unknown. Here, we show that the N-glycosidase effector, which belongs to the STIR superfamily, hydrolyzes NAD+ during infection. Cryoelectron microscopy (cryo-EM) analysis shows that the msDNA stabilizes a filament that cages the effector in a low-activity state in which ADPr, a NAD+ hydrolysis product, is covalently linked to the catalytic E106 residue. Mutations shortening the msDNA induce filament disassembly and the effector's toxicity, underscoring the msDNA role in immunity. Furthermore, we discovered a phage-encoded Retron-Eco1 inhibitor (U56) that binds ADPr, highlighting the intricate interplay between retron systems and phage evolution. Our work outlines the structural basis of Retron-Eco1 defense, uncovering ADPr's pivotal role in immunity.
KW - ADP-ribosylation
KW - bacteria anti-phage defense
KW - bacterial immune systems
KW - biochemistry
KW - cryoelectron microscopy
KW - Ec86
KW - enzyme mechanisms
KW - NAD
KW - Retron-Eco1
KW - structural biology
U2 - 10.1016/j.molcel.2024.05.001
DO - 10.1016/j.molcel.2024.05.001
M3 - Journal article
C2 - 38788717
AN - SCOPUS:85194743036
VL - 84
SP - 2185-2202.e12
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 11
ER -
ID: 394479163