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Type IV systems are the most enigmatic category of CRISPR systems. Type IV systems are most frequently found on plasmids, conjugative plasmid elements, and seldom in phage genomes (Pinilla‐Redondo et al. 2020), and typically lack genes involved in adaptation (Cas1, Cas2, and Cas4) or nucleolytic degradation Figure 3.2, and frequently even without the CRISPR arrays (Makarova et al. 2019). Subtype IV‐C, a recently discovered CRISPR system of Thermoflexia bacterium, contains a large subunit (LS or csf1) gene with putative HD nuclease domain, providing the only suggestion that some of the type IV systems might retain nuclease activity (Makarova et al. 2019). Recently, a striking bias toward plasmid sequences as spacers (in contrast to other systems, which predominantly share homology with viral genomes) has suggested that type IV might have a role in plasmid maintenance and competition (Faure et al. 2019a; Newire et al. 2020; Pinilla‐Redondo et al. 2020), whether this is true remains to be experimentally established.

Bioinformatic analyses have observed that type IV systems are frequently found together with type I systems, indicating a potential crosstalk between the two systems. Indeed, PAM, repeat, and leader sequences are nearly identical between the co‐occurring systems (Pinilla‐Redondo et al. 2020), suggesting that type IV systems can be viewed as minimal Cas systems that can rely on the adaptation machinery from “helper” type I system. Recently, a structure of type IV effector complex has revealed a sea cucumber‐like structure, with seven Cas7‐like subunits forming the backbone and interacting with crRNA (inducing a kink in the RNA every sixth nucleotide much like type I Cascade), with five Cas11 forming the belly of the structure (Zhou et al. 2020). Cas6 protein in type IV systems is responsible for processing and binding to crRNA (Ozcan et al. 2019), much like in type I. However, when components of the Mycobacterium sp. type IV system were co‐expressed in E. coli, it was found that crRNA originated from a wide range of sources, including from the plasmid harboring the type IV system, but also from rRNA, tRNA, and other noncoding small RNA. This suggests that there might be indeed crosstalk between the hosts and plasmid‐borne CRISPR systems; however, the apparent lack of specificity in processing/assembling crRNA–effector complex does not support a role in nuclease‐mediated immunity. The fact that type IV systems are frequently accompanied by genes with a potential role in other types of bacterial defense systems, such as cysH or ART gene, supports the notion that this type of system has been co‐opted for plasmid or phage maintenance, rather than their depletion (Faure et al. 2019b). Further studies are needed to unravel the role (if any) of these systems.