Cyclic oligoadenylate signalling mediates Mycobacterium tuberculosis CRISPR defence.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

Adenine Nucleotides/*genetics ; CRISPR-Cas Systems/*genetics ; Clustered Regularly Interspaced Short Palindromic Repeats/*genetics ; Mycobacterium tuberculosis/*genetics ; Oligoribonucleotides/*genetics; Adaptive Immunity/immunology ; Adenine Nucleotides/biosynthesis ; CRISPR-Associated Proteins/genetics ; CRISPR-Cas Systems/immunology ; Clustered Regularly Interspaced Short Palindromic Repeats/immunology ; Interspersed Repetitive Sequences/genetics ; Interspersed Repetitive Sequences/immunology ; Mycobacterium tuberculosis/immunology ; Oligoribonucleotides/biosynthesis ; Prokaryotic Cells/immunology ; RNA Cleavage/genetics ; RNA Cleavage/immunology ; Signal Transduction/genetics ; Signal Transduction/immunology

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.
(© The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.)

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BB/S000313/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council

0 (Adenine Nucleotides)
0 (CRISPR-Associated Proteins)
0 (Oligoribonucleotides)
61172-40-5 (2',5'-oligoadenylate)

Date Created: 20190809 Date Completed: 20191210 Latest Revision: 20230606

20230606

PMC6755085

10.1093/nar/gkz676

31392987