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Type III CRISPR–Cas systems produce cyclic oligoadenylate second messengers

Author

Listed:
  • Ole Niewoehner

    (University of Zurich)

  • Carmela Garcia-Doval

    (University of Zurich)

  • Jakob T. Rostøl

    (Laboratory of Bacteriology, The Rockefeller University)

  • Christian Berk

    (Institute for Pharmaceutical Sciences)

  • Frank Schwede

    (BIOLOG Life Science Institute GmbH)

  • Laurent Bigler

    (University of Zurich)

  • Jonathan Hall

    (Institute for Pharmaceutical Sciences)

  • Luciano A. Marraffini

    (Laboratory of Bacteriology, The Rockefeller University)

  • Martin Jinek

    (University of Zurich)

Abstract

In many prokaryotes, type III clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated (Cas) systems detect and degrade invasive genetic elements by an RNA-guided, RNA-targeting multisubunit interference complex. The CRISPR-associated protein Csm6 additionally contributes to interference by functioning as a standalone RNase that degrades invader RNA transcripts, but the mechanism linking invader sensing to Csm6 activity is not understood. Here we show that Csm6 proteins are activated through a second messenger generated by the type III interference complex. Upon target RNA binding by the interference complex, its Cas10 subunit converts ATP into a cyclic oligoadenylate product, which allosterically activates Csm6 by binding to its CRISPR-associated Rossmann fold (CARF) domain. CARF domain mutations that abolish allosteric activation inhibit Csm6 activity in vivo, and mutations in the Cas10 Palm domain phenocopy loss of Csm6. Together, these results point to an unprecedented mechanism for regulation of CRISPR interference that bears striking conceptual similarity to oligoadenylate signalling in mammalian innate immunity.

Suggested Citation

  • Ole Niewoehner & Carmela Garcia-Doval & Jakob T. Rostøl & Christian Berk & Frank Schwede & Laurent Bigler & Jonathan Hall & Luciano A. Marraffini & Martin Jinek, 2017. "Type III CRISPR–Cas systems produce cyclic oligoadenylate second messengers," Nature, Nature, vol. 548(7669), pages 543-548, August.
    • Handle: RePEc:nat:nature:v:548:y:2017:i:7669:d:10.1038_nature23467
    DOI: 10.1038/nature23467
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    Cited by:

    1. Evan A. Schwartz & Tess M. McBride & Jack P. K. Bravo & Daniel Wrapp & Peter C. Fineran & Robert D. Fagerlund & David W. Taylor, 2022. "Structural rearrangements allow nucleic acid discrimination by type I-D Cascade," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Ning Cui & Jun-Tao Zhang & Zhuolin Li & Xiao-Yu Liu & Chongyuan Wang & Hongda Huang & Ning Jia, 2022. "Structural basis for the non-self RNA-activated protease activity of the type III-E CRISPR nuclease-protease Craspase," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Anna Nemudraia & Artem Nemudryi & Murat Buyukyoruk & Andrew M. Scherffius & Trevor Zahl & Tanner Wiegand & Shishir Pandey & Joseph E. Nichols & Laina N. Hall & Aidan McVey & Helen H. Lee & Royce A. Wi, 2022. "Sequence-specific capture and concentration of viral RNA by type III CRISPR system enhances diagnostic," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. 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.

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