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An infallible inhibitor of Cas13
CRISPR-Cas13 protects bacterial populations from viral infections by indiscriminately destroying the RNA of the cell and its invader, simultaneously arresting the growth of infected hosts and the spread of the virus. This response is mediated by the Cas13 nuclease, which unleashes massive RNA degradation after recognition of viral transcripts that are complementary to its guide RNA. Meeske et al. discovered AcrVIA1, a viral-encoded inhibitor that binds to Cas13 to occlude the RNA guide and prevent the activation of the nuclease (see the Perspective by Barrangou and Sontheimer). As opposed to inhibitors of DNA-cleaving CRISPR-Cas systems, which require multiple infections to neutralize all Cas nucleases of the host, production of AcrVIA1 by a single virus is sufficient to overcome the CRISPR-Cas13 response.
Abstract
The CRISPR RNA (crRNA)–guided nuclease Cas13 recognizes complementary viral transcripts to trigger the degradation of both host and viral RNA during the type VI CRISPR-Cas antiviral response. However, how viruses can counteract this immunity is not known. We describe a listeriaphage (ϕLS46) encoding an anti-CRISPR protein (AcrVIA1) that inactivates the type VI-A CRISPR system of Listeria seeligeri. Using genetics, biochemistry, and structural biology, we found that AcrVIA1 interacts with the guide-exposed face of Cas13a, preventing access to the target RNA and the conformational changes required for nuclease activation. Unlike inhibitors of DNA-cleaving Cas nucleases, which cause limited immunosuppression and require multiple infections to bypass CRISPR defenses, a single dose of AcrVIA1 delivered by an individual virion completely dismantles type VI-A CRISPR-mediated immunity.
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