It is necessary that an immune system can distinguish between foreign material and components that belong to us, this is important because it would help to protect us against various types of pathogens and prevents autoimmunity. Normally, an immune system would be strictly controlled so that the immune system is only activated in the presence of foreign material, this is so that only foreign material is specifically targeted.
The CRISPR-Cas system is used in bacteria and archaea as a defence mechanism against phages. The first step in the defence mechanism is whereby DNA from the phage is acquired and placed into the bacterial genome at the CRISPR locus to form the immune memory. Therefore, when the bacteria is attacked again by the same phage, the CRISPR-Cas system will remember it and be able to remove the phage by using a guide RNA and Cas. Even though we have learned a lot about the CRISPR-Cas systems there is still more to learn. We still do not understand how the CRISPR-Cas systems are regulated inside these single-celled organisms. We do know about the protospacer adjacent motif (PAM), it is a way in which the CRISPR-Cas system can distinguish itself from foreign material. This is because PAM sequences are not present in the bacterial CRISPR locus and therefore, PAM serves to prevent autoimmunity.
Researchers from the Johns Hopkins University have released a study in bioRxiv. The researchers wanted to determine how the CRISPR-Cas system is controlled to prevent autoimmunity and how targeting of foreign material is improved. The research group found that the CRISPR-Cas system is capable of regulating itself. Two forms of tracrRNA are produced, a long and short form. The short form tracrRNA is involved in producing crRNA and thus is used to disrupt sequences of invading phages. The long-form of tracrRNA is produced but its role was unknown until now. The researchers found that the long-form tracrRNA changes its state to become a single guide RNA, and then guides Cas9 to the Cas operon to inhibit the gene expression of the CRISPR-Cas components. In this state, the CRISPR system still works but in a less active state. The removal of long-form tracRNA causes substantial activation of the Cas genes, tracrRNAs, crRNAs, and boosts the immune function of the CRISPR-Cas system too. Although this boost may help to remove invading phages, it also results in autoimmune toxicity. Therefore, long-form tracrRNA serves as a vital regulatory mechanism in the CRISPR-Cas system.