Scientists at the Weizmann Institute of Science have discovered a function that stops severe infections. The discovery could help combat antibiotic resistance.
Just as humans generate mountains of garbage, our cells are constantly discarding proteins that are damaged or no longer needed.
The cellular waste disposal system called the proteasome is best known for its central role in protein degradation and recycling, but as early as the 1990s, it was shown that the products of this process (short protein sequences called peptides) can be displayed on cell surfaces, helping the immune system identify threats.
In a study published today in Nature, Professor Yifat Merbl's laboratory at the Weizmann Institute of Science reports the discovery of a surprising immunological mechanism involving the proteasome.
The team discovered that some of the peptides released by the proteasome during protein breakdown are capable of killing bacteria. These findings expand our understanding of the body's innate defenses and offer new hope for addressing the growing threat of antibiotic resistance.
Several years ago, scientists in Merbl's lab at Weizmann's Department of Systems Immunology developed a breakthrough technology that allowed them to "dumpster dive" inside the proteasome, a complex molecular machine composed of numerous proteins. Using this advanced tool, the researchers tracked proteasomes in various diseases, including lupus and cancer, and accumulated vast amounts of data on degraded protein fragments.
"We analyzed all the data in depth and asked ourselves: could the degradation products play an additional role besides being presented to the immune system?" says Merbl about the starting point of the new study. To their surprise, the researchers discovered that many of these degradation products matched sequences previously identified as antimicrobial peptides—critical components of the innate immune system, which acts as the body's first line of defense against bacteria, viruses, and parasites.
For years, it was known that these peptides could be generated by protein-cleaving enzymes called proteases, which "release" them from proteins so they can become active. However, new findings from Merbl's lab have shown that these peptides can be activated by proteasomes. In fact, the study revealed that the proteasome itself constantly produces these peptides as part of its routine activity, and that this production increases significantly during bacterial infections.
“Until now, we knew nothing about the connection between proteasome products and the production of these peptides,” says Merbl. “In light of our findings, we conducted a comprehensive series of experiments that demonstrated that proteasomes are key to this defense system.” In one experiment on human cells, the researchers inhibited proteasomes in one group of cells and left them intact in the other group; when the cells were infected with Salmonella, the invading bacteria thrived in the group lacking active proteasomes. In another experiment, bacteria thrived when the proteasome functioned normally, but the peptides produced within it were destroyed.
The effectiveness of the peptides was also demonstrated in mice infected with bacteria that cause pneumonia and sepsis, a life-threatening disease triggered by an immune response to a severe infection. Experiments on these mice showed that treatment with a proteasome-derived peptide significantly reduced the number of bacteria, decreased tissue damage, and even improved survival rates. The results surprised the researchers for two reasons.
First, they showed that a single peptide that the body produces naturally can be effective against a life-threatening disease when administered in large quantities. Second, the treatment results were comparable to those of strong antibiotics in clinical use.
However, what excited the researchers most was the realization that bacterial infection causes the proteasome to enter “turbo mode.” “We saw that infection causes the proteasome to change its protein-cleaving mode, which ‘favors’ the production of peptides with antibacterial properties,” Merbl says. When the researchers tried to explain what caused this change, one hour after infection, they identified proteasomes with a control unit called PSME3 and discovered that this subunit was responsible for prioritizing the production of such peptides. When they prevented the proteasomes from using this control subunit, the bacteria were less damaged, highlighting the importance of the proteasome as a first line of defense against infection.
“The ability to track how proteasome activity changes in response to a bacterial infection was based on technology we developed several years ago,” explains PhD student Karin Goldberg, who led the project. “The turning point came when we saw that the proteasome’s peptide-cleaving activity changed during infection. That’s when we realized we had uncovered a previously unknown immunological mechanism.”
The researchers then asked a broader question: how many hidden antimicrobial peptides might be lurking in human proteins? Using an algorithm to analyze all the proteins the human body produces, they identified peptides with potential antibacterial properties in 92 percent of human proteins. Their simulations revealed more than 270,000 previously unknown peptides that could be released by the proteasome, representing a huge untapped reservoir of natural antimicrobial agents.
“This peptide database opens a new frontier for the development of personalized treatments against infections and other medical conditions,” Merbl explains. For example, natural peptides could be tailored to strengthen immune defenses in patients with weakened immunity, such as organ transplant recipients or cancer patients. Furthermore, as antibiotic resistance continues to pose a significant public health challenge, the study's findings not only redefine our understanding of cellular immunity but also pave the way for innovative therapies based on natural mechanisms.
No comments:
Post a Comment