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Phage anti-CBASS and anti-Pycsar nucleases subvert bacterial immunity

Author

Listed:
  • Samuel J. Hobbs

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Tanita Wein

    (Weizmann Institute of Science)

  • Allen Lu

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Benjamin R. Morehouse

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Julia Schnabel

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Azita Leavitt

    (Weizmann Institute of Science)

  • Erez Yirmiya

    (Weizmann Institute of Science)

  • Rotem Sorek

    (Weizmann Institute of Science)

  • Philip J. Kranzusch

    (Harvard Medical School
    Dana-Farber Cancer Institute
    Parker Institute for Cancer Immunotherapy at Dana-Farber Cancer Institute)

Abstract

The cyclic oligonucleotide-based antiphage signalling system (CBASS) and the pyrimidine cyclase system for antiphage resistance (Pycsar) are antiphage defence systems in diverse bacteria that use cyclic nucleotide signals to induce cell death and prevent viral propagation1,2. Phages use several strategies to defeat host CRISPR and restriction-modification systems3–10, but no mechanisms are known to evade CBASS and Pycsar immunity. Here we show that phages encode anti-CBASS (Acb) and anti-Pycsar (Apyc) proteins that counteract defence by specifically degrading cyclic nucleotide signals that activate host immunity. Using a biochemical screen of 57 phages in Escherichia coli and Bacillus subtilis, we discover Acb1 from phage T4 and Apyc1 from phage SBSphiJ as founding members of distinct families of immune evasion proteins. Crystal structures of Acb1 in complex with 3′3′-cyclic GMP–AMP define a mechanism of metal-independent hydrolysis 3′ of adenosine bases, enabling broad recognition and degradation of cyclic dinucleotide and trinucleotide CBASS signals. Structures of Apyc1 reveal a metal-dependent cyclic NMP phosphodiesterase that uses relaxed specificity to target Pycsar cyclic pyrimidine mononucleotide signals. We show that Acb1 and Apyc1 block downstream effector activation and protect from CBASS and Pycsar defence in vivo. Active Acb1 and Apyc1 enzymes are conserved in phylogenetically diverse phages, demonstrating that cleavage of host cyclic nucleotide signals is a key strategy of immune evasion in phage biology.

Suggested Citation

  • Samuel J. Hobbs & Tanita Wein & Allen Lu & Benjamin R. Morehouse & Julia Schnabel & Azita Leavitt & Erez Yirmiya & Rotem Sorek & Philip J. Kranzusch, 2022. "Phage anti-CBASS and anti-Pycsar nucleases subvert bacterial immunity," Nature, Nature, vol. 605(7910), pages 522-526, May.
  • Handle: RePEc:nat:nature:v:605:y:2022:i:7910:d:10.1038_s41586-022-04716-y
    DOI: 10.1038/s41586-022-04716-y
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    Cited by:

    1. Aa Haeruman Azam & Kohei Kondo & Kotaro Chihara & Tomohiro Nakamura & Shinjiro Ojima & Wenhan Nie & Azumi Tamura & Wakana Yamashita & Yo Sugawara & Motoyuki Sugai & Longzhu Cui & Yoshimasa Takahashi &, 2024. "Evasion of antiviral bacterial immunity by phage tRNAs," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    2. Chia-Shin Yang & Tzu-Ping Ko & Chao-Jung Chen & Mei-Hui Hou & Yu-Chuan Wang & Yeh Chen, 2023. "Crystal structure and functional implications of cyclic di-pyrimidine-synthesizing cGAS/DncV-like nucleotidyltransferases," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Ruiwen Wang & Qi Xu & Zhuoxi Wu & Jialu Li & Hao Guo & Tianzhui Liao & Yuan Shi & Ling Yuan & Haishan Gao & Rong Yang & Zhubing Shi & Faxiang Li, 2024. "The structural basis of the activation and inhibition of DSR2 NADase by phage proteins," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    4. Shuangshuang Wang & Sirong Kuang & Haiguang Song & Erchao Sun & Mengling Li & Yuepeng Liu & Ziwei Xia & Xueqi Zhang & Xialin Wang & Jiumin Han & Venigalla B. Rao & Tingting Zou & Chen Tan & Pan Tao, 2024. "The role of TIR domain-containing proteins in bacterial defense against phages," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Ning Duan & Emily Hand & Mannuku Pheko & Shikha Sharma & Akintunde Emiola, 2024. "Structure-guided discovery of anti-CRISPR and anti-phage defense proteins," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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