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Bacterial cGAS-like enzymes synthesize diverse nucleotide signals

Author

Listed:
  • Aaron T. Whiteley

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • James B. Eaglesham

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Carina C. de Oliveira Mann

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Benjamin R. Morehouse

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Brianna Lowey

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Eric A. Nieminen

    (Dana-Farber Cancer Institute)

  • Olga Danilchanka

    (Harvard Medical School
    Merck & Co. Inc.)

  • David S. King

    (University of California, Berkeley)

  • Amy S. Y. Lee

    (Brandeis University)

  • John J. Mekalanos

    (Harvard Medical School)

  • Philip J. Kranzusch

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

Abstract

Cyclic dinucleotides (CDNs) have central roles in bacterial homeostasis and virulence by acting as nucleotide second messengers. Bacterial CDNs also elicit immune responses during infection when they are detected by pattern-recognition receptors in animal cells. Here we perform a systematic biochemical screen for bacterial signalling nucleotides and discover a large family of cGAS/DncV-like nucleotidyltransferases (CD-NTases) that use both purine and pyrimidine nucleotides to synthesize a diverse range of CDNs. A series of crystal structures establish CD-NTases as a structurally conserved family and reveal key contacts in the enzyme active-site lid that direct purine or pyrimidine selection. CD-NTase products are not restricted to CDNs and also include an unexpected class of cyclic trinucleotide compounds. Biochemical and cellular analyses of CD-NTase signalling nucleotides demonstrate that these cyclic di- and trinucleotides activate distinct host receptors and thus may modulate the interaction of both pathogens and commensal microbiota with their animal and plant hosts.

Suggested Citation

  • Aaron T. Whiteley & James B. Eaglesham & Carina C. de Oliveira Mann & Benjamin R. Morehouse & Brianna Lowey & Eric A. Nieminen & Olga Danilchanka & David S. King & Amy S. Y. Lee & John J. Mekalanos & , 2019. "Bacterial cGAS-like enzymes synthesize diverse nucleotide signals," Nature, Nature, vol. 567(7747), pages 194-199, March.
    • Handle: RePEc:nat:nature:v:567:y:2019:i:7747:d:10.1038_s41586-019-0953-5
    DOI: 10.1038/s41586-019-0953-5
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    Cited by:

    1. 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.
    2. Xia Li & Wenfang Yin & Junjie Desmond Lin & Yong Zhang & Quan Guo & Gerun Wang & Xiayu Chen & Binbin Cui & Mingfang Wang & Min Chen & Peng Li & Ya-Wen He & Wei Qian & Haibin Luo & Lian-Hui Zhang & Xue, 2023. "Regulation of the physiology and virulence of Ralstonia solanacearum by the second messenger 2′,3′-cyclic guanosine monophosphate," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Shirin Fatma & Arpita Chakravarti & Xuankun Zeng & Raven H. Huang, 2021. "Molecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3′,2′-cGAMP as the second messenger," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    4. Mei-Hui Hou & Chao-Jung Chen & Chia-Shin Yang & Yu-Chuan Wang & Yeh Chen, 2024. "Structural and functional characterization of cyclic pyrimidine-regulated anti-phage system," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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