Regulation of CRISPR-Cas adaptive immune systems

•CRISPR-Cas systems provide adaptive defense against invading genetic elements.•Controlling CRISPR-Cas activity enables optimization of the immune response.•CRISPR-Cas regulation involves an integrated network that acts at multiple levels.•Regulatory strategies can be conserved between different systems and strains.•Diverse regulatory mechanisms exist that likely reflect varied selective pressures.

CRISPR-Cas systems are prokaryotic immune systems that allow defense against invasion by foreign genetic elements. Through the acquisition of genetic memory representing prior exposure, the CRISPR-Cas machinery identifies complementary nucleic acids and mediates their destruction. Since their discovery, CRISPR-Cas research has exploded, with major progress into their mechanism and biotechnological application. In contrast, we are only beginning to understand how CRISPR-Cas activity is regulated. Recent studies have uncovered both conserved regulatory pathways, in addition to more specific mechanisms. Identifying the stimuli linking invasion with CRISPR-Cas activation will be essential in unraveling their ecological roles, evolutionary success and might offer strategies to control immunity for particular applications. We highlight factors impinging on CRISPR-Cas regulation across diverse bacterial and archaeal species.