CRISPR-Cas regulates expression of embedded anti-phage defence systems

Bacteria utilize diverse defence systems to protect against harmful foreign DNA such as bacteriophages^1,2, but how these systems coordinate with each other remains poorly understood. Here we uncover CRISIS (CRISPR-supervised immune system), a widespread regulatory paradigm whereby type I CRISPR-Cas loci embed and transcriptionally modulate diverse innate defences. Small non-canonical CRISPR RNA (crRNA)-like RNAs guide the I-C CRISPR-associated complex for antiviral defence (Cascade) effector complex to inhibit promoters of diverse immune cassettes-including composite multi-system clusters-enabling their basal expression for antiviral activity while mitigating fitness costs associated with hyperactivation, such as host growth impairment or exclusion of beneficial plasmids. When CRISPR-Cas is compromised by mutation or anti-CRISPR proteins, there is a burst in transcription of these embedded defence systems, leading to higher-level innate immunity at the expense of host fitness. Together, adaptive CRISPR-Cas systems orchestrate diverse innate immune systems into a layered defence network, comprising a prokaryotic 'immunity guard' strategy.