Bacteria utilize diverse defence systems to protect against harmful foreign DNA such as bacteriophages1,2, 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.
