Bacteriophages suppress CRISPR–Cas immunity using RNA-based anti-CRISPRs

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Many bacteria use CRISPR–Cas systems to combat mobile genetic elements, such as bacteriophages and plasmids1. In turn, these invasive elements have evolved anti-CRISPR proteins to block host immunity2,3. Here we unveil a distinct type of CRISPR–Cas Inhibition strategy that is based on small non-coding RNA anti-CRISPRs (Racrs). Racrs mimic the repeats found in CRISPR arrays and are encoded in viral genomes as solitary repeat units4. We show that a prophage-encoded Racr strongly inhibits the type I-F CRISPR–Cas system by interacting specifically with Cas6f and Cas7f, resulting in the formation of an aberrant Cas subcomplex. We identified Racr candidates for almost all CRISPR–Cas types encoded by a diverse range of viruses and plasmids, often in the genetic context of other anti-CRISPR genes5. Functional testing of nine candidates spanning the two CRISPR–Cas classes confirmed their strong immune inhibitory function. Our results demonstrate that molecular mimicry of CRISPR repeats is a widespread anti-CRISPR strategy, which opens the door to potential biotechnological applications6.
OriginalsprogEngelsk
TidsskriftNature
Vol/bind623
Udgave nummer7987
Sider (fra-til)601-607
Antal sider7
ISSN0028-0836
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We thank members of our laboratories for helpful discussions, with special mention of N. Birkholz, S. Meaden, L. M. Smith, U. Trivedi, T. R. Blower, I. Beck, J. Bondy-Denomy, A. Carabias del Rey and M. Rodriguez-Mestre for valuable input. We thank S. A. Jackson for providing a Cas expression plasmid. We apologize to authors whose work we were unable to cite owing to referencing restrictions. R.P.-R. was supported by the Lundbeck Foundation (grant R347-2020-2346) and a Danish Pasteur Society travel grant 2022. S.J.S. and R.P.-R. were supported by Industrial Biotechnology and Environmental Biotechnology project grants 2020 (NNF20OC0064822). D.M.-M. was supported by a University of Otago doctoral scholarship; R.D.F. and P.C.F. were supported by Bioprotection Aotearoa Centre of Research Excellence (Tertiary Education Commission, New Zealand) and a University of Otago Research Grant. P.C.F. was supported by an Experienced Researcher Fellowship from the Alexander von Humboldt Foundation. J.S.M and S.C.-W were supported by the Villum Foundation (grant 00028304).

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© 2023, The Author(s).

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