Cyclic oligoadenylate signalling mediates Mycobacterium tuberculosis CRISPR defence

Sabine Grüschow, Januka S Athukoralage, Shirley Graham, Tess Hoogeboom, Malcolm F White

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43 Citations (Scopus)
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The CRISPR system provides adaptive immunity against mobile genetic elements (MGE) in prokaryotes. In type III CRISPR systems, an effector complex programmed by CRISPR RNA detects invading RNA, triggering a multi-layered defence that includes target RNA cleavage, licencing of an HD DNA nuclease domain and synthesis of cyclic oligoadenylate (cOA) molecules. cOA activates the Csx1/Csm6 family of effectors, which degrade RNA non-specifically to enhance immunity. Type III systems are found in diverse archaea and bacteria, including the human pathogen Mycobacterium tuberculosis. Here, we report a comprehensive analysis of the in vitro and in vivo activities of the type III-A M. tuberculosis CRISPR system. We demonstrate that immunity against MGE may be achieved predominantly via a cyclic hexa-adenylate (cA6) signalling pathway and the ribonuclease Csm6, rather than through DNA cleavage by the HD domain. Furthermore, we show for the first time that a type III CRISPR system can be reprogrammed by replacing the effector protein, which may be relevant for maintenance of immunity in response to pressure from viral anti-CRISPRs. These observations demonstrate that M. tuberculosis has a fully-functioning CRISPR interference system that generates a range of cyclic and linear oligonucleotides of known and unknown functions, potentiating fundamental and applied studies.
Original languageEnglish
Pages (from-to)9259-9270
Number of pages12
JournalNucleic Acids Research
Issue number17
Early online date8 Aug 2019
Publication statusPublished - 26 Sept 2019


  • Crystal-structure
  • DNA cleavage
  • CMS complex
  • Protein
  • Degradation
  • Immunity
  • System
  • CSX1


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