The main function of the CRISPR-Cas system, an innovative tool that scientists are currently using for gene editing, is to protect bacteria from threats such as viruses called bacteriophages. Researchers have continued to study all types of CRISPR-Cas systems (two classes, seven types, and 46 subtypes have been identified to date) to understand all their functions.
A new paper from the lab of Yang Zhang, Ph.D., associate professor of biochemistry, microbiology, and immunology at the University of Michigan Medical School, and her colleagues and collaborators reveal a previously poorly recognized feature of the type I CRISPR-Cas system in the bacterium Neisseria: the presence of additional embedded innate immune genes.
The group discovered that type I CRISPR acts as a manager that controls the expression of these built-in defense systems.
Our central finding here is that bacterial antiphage defense systems can be organized into hierarchical regulatory hierarchies.
In our case, CRISPR-Cas acts as a commander in chief controlling the repression and derepression of other innate defense system genes hidden within the CRISPR-Cas locus. ”
Yan Zhang, Ph.D., Associate Professor of Biochemistry, Microbiology, and Immunology, University of Michigan School of Medicine
The study, co-led by Dr. Ming Li of the Institute of Microbiology, Chinese Academy of Sciences, was published in the journal nature.
Under normal circumstances, Zhang explained, activation of these defense genes is costly, and production of these defense genes must be suppressed to suppress bacterial growth. Such suppression is achieved by the CRISPR-Cas complex binding as a barrier to the promoter sequences of defense genes and preventing their transcription.
“CRISPR is the first line of defense during a phage infection, but if CRISPR is flawed or disarmed in some way, it will be unsuppressed and produce an explosion of innate defense systems as a backup weapon to annihilate the phage,” Zhang explained.
Of course, phages have their own tricks to evade CRISPR defenses, such as the use of peptide inhibitors designed to disable the Cas machinery. However, in the face of this multilayered defense hierarchy, Cas inhibitors are no longer sufficient to save the phage because they trigger the release of backup defenses that can kill the phage, Zhang says.
This new understanding of bacterial antiphage immunity could be exploited in several ways, she added. First, for industries that use bacteria, such as manufacturers of yogurt, fermented products, and biofuels, these insights could help engineer more robust and phage-resistant bacterial strains. Second, it could be useful in the development of phage therapy.
“To develop better phage therapies to kill antibiotic-resistant bacterial pathogens, we need to understand what hidden defense systems exist. Then we might be able to manipulate phages to outwit them.”
This work is Neisseria The genetics and phage platform established by former postdoc Dr. Feizhou Zhou and the work of current PhD student Xin Li in Zhang’s lab has made it possible to study the physiological significance of this regulation in the natural host.
“This has been a really fun collaboration,” Zhang added, crediting Lee and his team members for “initiating this project, inviting us to collaborate, and driving many important aspects of the discovery.”
sauce:
Michigan Medicine – University of Michigan
Reference magazines:
Shu, X. others. (2026). CRISPR-Cas controls the expression of integrated antiphage defense systems. nature. DOI: 10.1038/s41586-026-10833-9. https://www.nature.com/articles/s41586-026-10833-9
