A study at the Weizmann Institute of Science in Rehovot has expanded our understanding of the body’s innate defenses and provides a new path into fighting the growing threat of antibiotic resistance.
Much like humans generate huge piles of garbage, our cells are constantly disposing of 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 far back as three decades ago, it was shown that products of this process – short protein sequences called peptides – can be displayed on the cell surfaces, helping the immune system to identify threats.
Indeed, as immune cells patrol the body, they check out protein pieces called antigens that are generated when proteins are sent to degradation, and these pieces are presented on the surface of cells. When an antigen pattern looks suspicious, the immune system “hits delete” and eradicates the cell.
The study, just published in the prestigious journal Nature and carried out in the lab of Prof. Yifat Merbl in the Systems Immunology Department, uncovered a surprising immune mechanism involving the proteasome. They discovered that some of the peptides, released upon protein breakdown in the proteasome, are capable of direct killing of bacteria.
A few years ago, the Weizmann scientists developed an innovative technology that made it possible to “dumpster dive” within the proteasome, a complex molecular machine composed of numerous proteins to track proteasomal degradation in the context of human diseases.
Using this technology, they previously identified a role for altered proteasome activity, which allowed cancer cells to evade the immune system’s watchful gaze.
Now, based on data gathered using this system, they have identified a new role for proteasomally-cleaved peptides as a first line of defense against bacterial infection, serving as “natural antibiotics” that are made by the body.
“We took a broad look at all the data and asked ourselves – could the products of the degradation play an additional role, beyond their role in being presented to the immune system?” Merbl told The Jerusalem Post.
To their surprise, the researcher team found that many of these degradation products matched sequences previously identified as antimicrobial peptides – critical components of the innate immune system that act as the body’s first line of defense against bacteria, viruses, and parasites.
“We started by confirming the ability of such proteasomally-cleaved peptides, identified in humans, to fight bacteria and also confirmed it in mice models of systemic infections,” Merbl said.
The researchers wondered how many hidden antimicrobial peptides might be lurking within human proteins. Using an algorithm to analyze all the proteins made by the human body, they identified peptides with potential antibacterial properties in 92% of human proteins, reaching an estimate of over 270,000 previously unknown peptides that could potentially be released upon proteins’ breakdown, representing a huge untapped reservoir of natural antimicrobial agents.
For years, it was known that such peptides may be generated by protein-cutting enzymes called proteases that “released” them from proteins so they could become active, but the new findings of her lab have shown that such peptides may 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 ramps up significantly during bacterial infections.
“Until now, we knew nothing about this new role of the proteasome and the production of such defense peptides,” explained Merbl – who after an extended military service as an Israel Air Force officer, earned a bachelor’s of science degree in Computational Biology at Bar-Ilan University and then continued for a Masters in Immunology at the Weizmann Institute of Science and PhD at Harvard University.
“In light of our findings, we conducted an extensive series of experiments showing that the proteasomes are key to this defense system.”
Process of the experiment
In one experiment conducted on human cells, they inhibited the proteasomes in one group of cells and left them untouched in the other group; when the cells were infected with salmonella bacteria – produced by eating raw or undercooked meat, poultry, and eggs or by drinking unpasteurized milk and causing diarrhea, fever, and stomach cramps – the invading bacteria thrived in the group that lacked 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 shown in mice infected with bacteria that cause pneumonia and sepsis, a life-threatening condition triggered by an immune response to severe infection.
Experiments in these mice showed that treatment with a proteasome-derived peptide significantly reduced the number of bacteria, lessened tissue damage, and even improved survival rates.
The results surprised the researchers when they showed that a single peptide that is naturally made by the body can prove effective against a life-threatening condition when administered in large amounts, and the treatment’s results were comparable to those of giving strong antibiotics to the mice.
The researchers were most excited, however, when they realized that bacterial infection sends the proteasome into “turbo mode.”
“We saw that infection causes the proteasome to change its protein-cutting mode, ‘favoring’ the production of peptides with antibacterial properties,” Merbl added.
“The turning point came when we saw that the proteasome’s peptide-“cutting activity changed during infection, and we realized we had uncovered a previously unknown immune mechanism,” explained doctoral student Karin Goldberg, who led the project.
“Natural peptides could be tailored to strengthen immune defenses in patients with weakened immunity, including organ transplant recipients or cancer patients. As antibiotic resistance continues to pose a major 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.”
“Yet, it remains to determine whether we will have similar effects when given to patients, and this may take a lot of time”, Merbl mentioned.
Beyond the clinical implications, Merbl says that the greatest thrill was discovering a fundamental cellular mechanism that is regulated by the proteasome and is different from anything previously known.
“This study highlights how technological innovation and basic research intertwine in unforeseen ways. Without the technology that allowed us to analyze the cellular trash, we wouldn’t have made this discovery, but when we developed this technology, we never imagined that we would uncover a new immune mechanism.”