Degenerated CRISPRs widely regulate Cas expression to balance immunity and cost

CRISPR RNAs (crRNAs) and Cas proteins together provide prokaryotes with adaptive immunity against genetic invaders. How Cas expression is fine-tuned to avoid energy burden while satisfying the dynamic need of crRNAs remains poorly understood. Here we experimentally demonstrated widespread degenerated mini-CRISPRs encode CreR (Cas-regulating) RNAs to mediate autorepression of type I-B, I-E and V-A Cas proteins, based on their partial complementarity to cas promoters. This autorepression decreases energy burden and autoimmune risks, thus mitigating the fitness cost on host cell, and remarkably, senses and responds to alterations in the volume of canonical crRNAs, which compete with CreR for Cas proteins. Moreover, CreR-guided Cas autorepression can be subverted by diverse anti-CRISPR (Acr) proteins that destruct Cas proteins, which in turn replenishes the weapon depot. Our data unveil a general degenerated crRNA-guided autorepression paradigm for diverse Cas effectors, which highlights the intricate (self-)regulation of CRISPR-Cas and its transcriptional counterstrategy against Acr attack. ### Competing Interest Statement The authors have declared no competing interest.