Structural mechanism of the Retron-Eco7 anti-phage defense system

Junichiro Ishikawa, Kanta Yoneyama, Aa Haeruman Azam, Asuteka Nagao, Yoshihisa Mitsuda, Ren Nakazaki, Kotaro Chihara, Masahiro Hiraizumi, Keitaro Yamashita, Tsutomu Suzuki, Kotaro Kiga () and Hiroshi Nishimasu ()
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Junichiro Ishikawa: The University of Tokyo, Department of Chemistry and Biotechnology, Graduate School of Engineering
Kanta Yoneyama: The University of Tokyo, Department of Chemistry and Biotechnology, Graduate School of Engineering
Aa Haeruman Azam: National Institute of Infectious Diseases, Research Center for Drug and Vaccine Development
Asuteka Nagao: The University of Tokyo, Department of Chemistry and Biotechnology, Graduate School of Engineering
Yoshihisa Mitsuda: The University of Tokyo, Department of Chemistry and Biotechnology, Graduate School of Engineering
Ren Nakazaki: The University of Tokyo, Department of Chemistry and Biotechnology, Graduate School of Engineering
Kotaro Chihara: National Institute of Infectious Diseases, Research Center for Drug and Vaccine Development
Masahiro Hiraizumi: The University of Tokyo, Department of Chemistry and Biotechnology, Graduate School of Engineering
Keitaro Yamashita: The University of Tokyo, Structural Biology Division, Research Center for Advanced Science and Technology
Tsutomu Suzuki: The University of Tokyo, Department of Chemistry and Biotechnology, Graduate School of Engineering
Kotaro Kiga: National Institute of Infectious Diseases, Research Center for Drug and Vaccine Development
Hiroshi Nishimasu: The University of Tokyo, Department of Chemistry and Biotechnology, Graduate School of Engineering

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Retrons are prokaryotic genetic elements involved in anti-phage defense and consist of a non-coding RNA, a reverse transcriptase (RT), and various effector proteins. Retron-Eco7 (previously known as Retron-Ec78) from Escherichia coli encodes two effector proteins (the PtuA ATPase and the PtuB nuclease) and degrades the host tRNATyr upon phage infection, thereby protecting host cells against invading phages. However, its defense mechanism remains elusive. Here, we report the cryo-electron microscopy (cryo-EM) structures of the Retron-Eco7 complex, comprising the RT, multicopy single-stranded DNA (msDNA), PtuA, and PtuB. The Retron-Eco7 structures reveal that the RT–msDNA complex associates with two PtuA–PtuB complexes, potentially inhibiting their nuclease activity and suppressing bacterial growth arrest prior to phage infection. Furthermore, the phage-encoded D15 nuclease acts as a trigger for the Retron-Eco7 system and cleaves the msDNA bound to the complex, facilitating the dissociation of PtuA–PtuB from RT–msDNA. Our data indicate that msDNA cleavage by D15 is the initial step required for the specific cleavage of the host tRNATyr by the PtuA–PtuB nuclease, which leads to abortive infection. Overall, this study provides mechanistic insights into the Retron-Eco7 system and highlights the diversity of prokaryotic anti-phage defense mechanisms.

Date: 2025
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DOI: 10.1038/s41467-025-66589-9

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