Cyclic oligoadenylate signalling mediates Mycobacterium tuberculosis CRISPR defence

Nucleic Acids Research
Sabine GrüschowMalcolm F White

Abstract

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 gen...Continue Reading

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Citations

Apr 30, 2020·Nucleic Acids Research·Aleksei SamolygoMalcolm F White
Nov 12, 2019·Frontiers in Microbiology·Yingjun Li, Nan Peng
Jan 17, 2020·Nature·Januka S AthukoralageMalcolm F White
Feb 9, 2021·Frontiers in Microbiology·Fengtao Huang, Bin Zhu
Dec 18, 2020·Nature Chemical Biology·Haridha ShivramJennifer A Doudna

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Methods Mentioned

BETA
restriction digest
PCR
gel filtration
size exclusion chromatography
electrophoresis
targeted mutation

Software Mentioned

ProtParam
OligoAnalyzer
ExPASy

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