Skip to main content
Sophie Binder, Gregor Hagelüken, Niels Schneberger in the laboratory

News categories: Publication

Gene scissors switch off with built-in timer

Bonn researchers clarify self-regulation of the immune response in the CRISPR bacterial defense system

CRISPR gene scissors, as new tools of molecular biology, have their origin in an ancient bacterial immune system. But once a virus attack has been successfully overcome, the cell has to recover. Researchers from the University Hospital Bonn (UKB) and the University of Bonn, in cooperation with researchers from the Institut Pasteur in France, have discovered a timer integrated into the gene scissors that enables the gene scissors to switch themselves off. The results of the study have been published in the renowned journal "Nucleic Acids Research".

Some bacteria have developed CRISPR gene scissors in response to attacks by so-called phages. This bacterial immune system recognizes the phage genetic material, destroys it and thus protects against viral attacks. When detecting phages, the type III variants of these immune systems produce messenger substances with cyclic oligoadenylates (cOAs), which the bacteria use to switch on a complex emergency plan. This ensures that a virus can be fought optimally and on a broad front. A research team led by PD Dr. Gregor Hagelueken from the Institute of Structural Biology at the UKB, who is a member of the Transdisciplinary Research Area (TRA) "Life & Health" and the Cluster of Excellence ImmunoSensation2 at the University of Bonn, discovered that the messenger substance cA4 produced by the gene scissors binds to a protein called CalpL. The protein scissors activated in this way trigger a signaling cascade that helps the cell to survive the viral attack.

The Bonn researchers had thus uncovered a completely new aspect of CRISPR systems, which can be easily reprogrammed for biotechnological and medical purposes. "These CRISPR-activated protein scissors that we discovered are a brand new tool in the toolbox of molecular biology," says Niels Schneberger, a doctoral student at the University of Bonn's Institute of Structural Biology at the UKB, who played a key role in the discovery of the CalpL protein.

 

Cellular recovery by limiting the antiviral response

"After a viral attack, however, it is crucial to eliminate the remaining cyclic oligoadenylates in order to terminate the antiviral reaction and return the cell to its normal state," says Sophie Binder, who shares the first authorship of the study with Schneberger and is also a doctoral student at the University of Bonn's Institute of Structural Biology at the UKB. In cooperation with researchers from the Institut Pasteur in Paris and the Kekulé Institute for Organic Chemistry and Biochemistry at the University of Bonn, the Bonn researchers have now been able to show that the so-called SAVED domain of the CalpL protease has a ring nuclease activity that cleaves cA4. "The protein therefore contains something like a molecular timer that switches off the immune reaction. By breaking down cA4 into linear fragments, the duration of the immune response is regulated, which enables a controlled return of the cell to normal conditions," says Binder.

A switchable protease such as CalpL is also of great interest for biotechnological applications. For example, it could be used as a molecular sensor. "The newly discovered ring nuclease activity is actually a disadvantage for such purposes," says PD Dr. Hagelueken. "However, in our study, we were also able to show how ring nuclease activity can be specifically inhibited so that the sensor does not switch itself off again.”

 

Sponsorship

The project was funded by the German Research Foundation (DFG) and the Open Access Publication Fund of the University of Bonn. In addition to the Institute of Structural Biology at the UKB, the Kekulé Institute of Organic Chemistry and Biochemistry at the University of Bonn and the Institut Pasteur, Paris, France, are also involved in the study.

 

Publication

Sophie C. Binder, Niels Schneberger, Marianne Engeser, Matthias Geyer, Christophe Rouillon, Gregor Hagelueken: The SAVED domain of the type III CRISPR protease CalpL is a ring nuclease; Nucleic Acids Research, 
DOI: https://doi.org/10.1093/nar/gkae676

Related news

Microglia interacting with T cells in the central nervous system of SPG15-deficient mice

News categories: Publication

Immune Cells Drive Congenital Paralysis Disease

Patients with spastic paraplegia type 15 develop movement disorders during adolescence that may ultimately require the use of a wheelchair. In the early stages of this rare hereditary disease the brain appears to play a major role by over-activating the immune system, as shown by a recent study published in the Journal of Experimental Medicine. The study was led by researchers at the University of Bonn and the German Center for Neurodegenerative Diseases (DZNE). These findings could also be relevant for Alzheimer's disease and other neurodegenerative conditions.
View entry
Scientists that contributed to the study

News categories: Publication

New way to prevent duodenal cancer

People with the hereditary disease familial adenomatous polyposis (FAP) have a greatly increased risk of developing a malignant tumor of the duodenum. Researchers at the University Hospital Bonn (UKB) and the Cluster of Excellence ImmunoSensation2 at the University of Bonn have now discovered a mechanism in the local immune system that can drive the development of cancer. They see this as a promising new approach to preventing duodenal carcinoma in people with FAP. The results have now been published in the journal "Nature Communications".
View entry
Kathrin Leppek Publication PM

News categories: Publication

Starting points for the control of protein synthesis

The research field of "cellular IRESes" lay dormant for decades, as there was no uniform standard of reliable methods for the clear characterization of these starting points for the ribosome-mediated control of gene expression. Researchers at the University Hospital Bonn (UKB) and the University of Bonn, in collaboration with Stanford University in California (USA), have now developed a toolbox as a new gold standard for this field. The results of their work have been published in The EMBO Journal.
View entry

Back to the news overview