In the laboratory of Prof. Yifat Marbel at the Weizmann Institute of Science, a vast reservoir of antimicrobial substances that are naturally produced in the body's cells as part of the process of breaking down proteins that have completed their function has been uncovered. The new discovery is good news in an era of increasing antibiotic resistance.
It’s not just us who produce mountains of waste every day – our cells are also constantly throwing away unwanted or useless proteins. The cellular waste disposal system, called the proteasome, is best known for its central role in breaking down and recycling proteins, but it was discovered in the 90s that its breakdown products – short protein sequences called peptides – can be displayed on the cell surface and used by the immune system to identify threats. In the study Published today in the scientific journal Nature A team of researchers from the Weizmann Institute of Science has revealed a surprising new immune mechanism in which the proteasome plays a central role. The mechanism revealed revealed that hundreds of thousands of peptides with the potential to destroy bacteria are hidden within most proteins in the body and can be released and put into action during the proteasome's protein degradation process. These findings are changing our understanding of our natural defenses and may be good news in an era of increasing antibiotic resistance.
A few years ago, Prof.'s laboratory Yifat Marble from the Department of Systemic Immunology has developed an innovative technology that allows for examining the contents of cellular waste found in the proteasome – that large protein complex to which proteins are sent for degradation. In this way, the laboratory has traced the exploits of proteasomes in various health conditions, such as lupus and cancer, and over time, they have accumulated a huge database of information about the products contained within them.
"We looked at all the data we had collected broadly, and asked ourselves – could the breakdown products have another function, beyond presenting them to the immune system?", says Prof. Marbel about the starting point for the new study. To their surprise, they discovered that many of the breakdown products were exactly the same as segments found in previous studies as antimicrobial peptides (AMPs) – important defense tools of the innate immune system, designed to serve as a first line of defense against bacteria, viruses and fungi. These peptides protect us from invaders in a continuous and rapid manner while the body recruits the acquired (adaptive) immune system for reinforcement. For years it was known that they were hidden inside other proteins and that cutting enzymes helped to "release" them so that they could go into action, but the new findings showed that they are actually continuously formed in the cell as part of the ongoing mechanism of protein degradation in the proteasome, and that their production is even increased during bacterial infection.
The results of the treatment were comparable to those obtained with strong antibiotic treatment.
"Until now, we knew nothing about the connection between the products of the proteasome and these peptides," says Prof. Marble. "Following the findings, we performed a comprehensive series of experiments that showed that proteasomes are central to this defense system." As part of these experiments, the researchers grew, among other things, human cells, and in one group of cells they suppressed the activity of the proteasomes, while in the other group they functioned normally. When the cells were infected with Salmonella bacteria, the invaders thrived in the group of cells where the proteasome was inactive; in another experiment, when the proteasome functioned normally but the peptides formed in it were destroyed, the bacteria actually managed to multiply. The effectiveness of the peptides was also demonstrated in live mice infected with a bacterium that leads to lung infections and even sepsis - a life-threatening medical condition caused by an immune response to a severe infection. In these experiments, too, treatment with the peptide led to a significant reduction in the number of bacteria, while minimizing damage to the lungs and other tissues, and even protected against death from generalized infection. The results surprised the researchers on two levels: First, they indicated that treatment with a single peptide that the body produces regularly can address an extreme threat when given in high amounts – and second, the results of the treatment were comparable to those obtained with treatment with a powerful antibiotic that is in clinical use.
But the researchers were particularly excited when they realized that bacterial infection puts the proteasome into "turbo" mode. "We observed that infection causes the proteasome to change the way it cuts proteins and 'prefer' the creation of peptides with properties that are suitable for killing bacteria," says Prof. Marble. When they examined what caused the change, they identified that within an hour of infection, proteasomes with a control unit called PSME3 were observed, and that this unit is responsible for prioritizing and creating antimicrobial peptides. When they prevented the proteasomes from recruiting this control unit, the damage to the bacteria decreased - a finding that highlights the importance of the proteasome as a first line of defense in cases of infection. "The ability to examine how proteasome activity changes in response to bacterial infection was based on the method we developed a few years ago, and the moment we saw that proteasome peptide cleavage changes in response to bacterial infection was a turning point - we realized that there was a new immune mechanism here," notes Karin Goldberg, the research student who led the project.
After becoming convinced that many of the peptides in the proteasome serve to protect the body, the researchers turned to asking a broader question: Are there potential protein cleavage products that may not have been identified as antimicrobial peptides so far? To answer this question, the researchers developed an algorithm that scanned all the proteins in the human body and checked how many of them contained hidden protein fragments with properties necessary for destroying bacteria. The results were impressive: potential antimicrobial peptides were found in about 92% of the proteins produced by the body. Using computer simulations, the researchers estimated how many of these hidden peptides might be cleaved and released by the proteasome. Once again, the numbers were astonishing: more than 270 cleavage products with the potential to serve as immune peptides. In doing so, the researchers created an unprecedented pool of peptides with previously unknown antimicrobial potential and constitute fertile ground for the development of many treatments.
"We may be able to leverage this peptide pool to develop a variety of personalized treatments against infections or, for example, to treat immunosuppressed individuals such as organ transplant recipients or cancer patients – who could receive treatment with natural peptides to boost their body's defense system," says Prof. Marble. In an era where antibiotic resistance threatens public health, the discovery of hundreds of thousands of potential immune peptides not only opens new horizons in the study of the body's defense systems, but also raises the possibility of developing innovative, more precise and safer drugs based on natural mechanisms.
Beyond the clinical significance, Prof. Marble notes that the real excitement is in discovering a fundamental cellular mechanism that is regulated by the proteasome and is different from what we knew so far. "This study highlights how technology development and basic research integrate with each other, in ways that are sometimes unpredictable - without the technology that allows us to look into the cellular trash cans, we could not have discovered this finding, but when we developed the technology, we could not have imagined that this is what we found."
The research groups of Prof. Zvi Hayuka from the Faculty of Agriculture, Food and Environment at the Hebrew University of Jerusalem; Prof. Nissan Issachar from the Faculty of Life Sciences at Bar-Ilan University; and Prof. Gee Lau from the University of Illinois in the USA also participated in the study.
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