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

News Florian Schmidt 09 2024

News categories: Publication

Central mechanism of inflammation decoded

The formation of pores by a particular protein, gasdermin D, plays a key role in inflammatory reactions. During its activation, an inhibitory part is split off. More than 30 of the remaining protein fragments then combine to form large pores in the cell membrane, which allow the release of inflammatory messengers. As methods for studying these processes in living cells have so far been inadequate, the sequence of oligomerization, pore formation and membrane incorporation has remained unclear until now.
View entry
Larvae of the fruit fly Drosophila (foreground) - have a kind of stretch sensor in the esophagus (grey structure in the middle). It reports swallowing processes to the brain. If food is ingested, special neurons of the enteric nervous system (red) release serotonin.

News categories: Publication

Swallowing triggers a feeling of elation

Researchers at the University of Bonn and the University of Cambridge have identified an important control circuit involved in the eating process. The study has revealed that fly larvae have special sensors, or receptors, in their esophagus that are triggered as soon as the animal swallows something. If the larva has swallowed food, they tell the brain to release serotonin. This messenger substance ensures that the larva continues to eat. The researchers assume that humans also have a very similar control circuit. The results were recently published in the journal “Current Biology.”
View entry
Dr. Andras Bilkei-Gorzo clarifies the influence of treatment with tetrahydrocannabinol on the metabolic switch mTOR

News categories: Publication

Anti-ageing and increased mental capacity through cannabis

A low-dose long-term administration of cannabis can not only reverse aging processes in the brain, but also has an anti-aging effect. Researchers from the University Hospital Bonn (UKB) and the University of Bonn together with a team from Hebrew University (Israel) have now been able to show this in mice. They found the key to this in the protein switch mTOR, whose signal strength has an influence on cognitive performance and metabolic processes in the entire organism. The results are now presented in the journal "ACS Pharmacology & Translation Science".
View entry

Back to the news overview