Nature: Textbooks need to be revised again! Scientists discover a "new continent" of the human immune system, and it turns out that 92% of proteins contain potential antimicrobial peptides |

*For medical professionals only

No matter what, I bet you never would have guessed it.

Humans could be walking "antibiotic factories."

Recently, a research team led by Yifat Merbl from the Weizmann Institute of Science published a groundbreaking study in the top journal Nature [1].

They first discovered that the cellular "garbage disposal" proteinase body is actually an important component of innate immunity. Specifically, among the annotated genes in the human body, at least 92% of genes contain the coding sequence for an antimicrobial peptide (AMP), which can potentially produce 270,872 different AMPs (almost like "universal soldiers").

Most importantly, the formation of these potential AMPs depends on the proteasome. Under normal conditions, the proteasome generates AMPs while cutting "garbage" proteins; when the body is infected, the proteasome tends to generate more AMPs during the process of cutting "garbage" proteins, causing a dramatic increase in the number of AMPs.

This discovery means that a new innate immune mechanism has been found (textbooks can't keep up). Such a vast natural "antibiotic arsenal" also provides new ideas for the development of new drugs in the field of infection control.

▲ Screenshot of the paper's homepage

As a professional team researching proteomics, infectious diseases are also a key focus area for Merbl Lab.

Antimicrobial peptides (AMPs) have been a hot topic of research in recent years, and scientists have discovered thousands of AMPs in various organisms. However, the current understanding of the existence of AMPs in the human body is still limited.

To investigate the situation of AMPs in the human proteome, Merbl's team compared the AMPs from different species with the human proteome and indeed identified 308 potential AMPs in 273 proteins, and these sequences are identical to those of previously reported AMPs with antibacterial activity.

Merbl's team briefly analyzed the characteristics of the above potential AMPs and found they have tissue specificity. Some well-studied AMPs are highly expressed in immune-related tissues and secretory tissues. However, it's strange that the potential AMPs found in the human body are located in special positions within proteins, making it difficult to release the AMPs.

It should be noted that many of the previously discovered AMPs are obtained by processing inactive AMP precursors through proteases. However, the potential AMPs found by Merbl's team in the human body are mainly distributed in complex protein structures. To release the AMPs, the proteins need to be unfolded and then cut, which proteases cannot do.

This phenomenon prompted Merbl's team to focus their research on the proteasome. They speculated that this organelle previously considered as a "garbage protein processor" might play an unknown role in innate immunity.

▲ Preliminary predicted antimicrobial peptides

Thus, based on the predicted proteasomal cleavage sites, they cleaved the human proteome to create a database containing approximately 34 million peptides.

Subsequently, they scored the above peptides according to the criteria for judging AMPs and found that about 1.2% of the peptides in the database showed AMP characteristics. They named these peptides "proteasome-derived defense peptides (PDDPs)." Given that the proteasome generates peptides at a rate of millions per minute, Merbl's team believes that under basal conditions, cells can obtain a large amount of potential protective peptides.

To test the hypothesis that proteasomes can indeed produce AMPs, Merbl's team infected cells with Salmonella typhimurium and found that if proteasome activity was inhibited, bacterial infections inside the cells increased. If the culture medium was treated with proteinase K, the bactericidal activity of the cell culture medium disappeared. This indicates that proteases can indeed produce AMPs.

▲ Proteases can indeed produce antimicrobial peptides

Next, Merbl's team synthesized the top ten proteasome-derived defense peptides (PDDPs), such as peptides from proteins PPP1CB, PSMG2, DCTN4, and DFNA5; they also synthesized less prominent peptides as negative controls, and used the well-studied antimicrobial peptide LK20 as a positive control.

Based on three Gram-positive bacteria and two Gram-negative bacteria, Merbl's team tested the antibacterial activity of the synthetic peptides. As shown in the figure below, the ten presumed proteasome-derived defense peptides inhibit bacterial growth to varying degrees in a dose-dependent manner; whereas the less prominent peptides had little antibacterial activity.

▲ Antibacterial activity of the top ten proteasome-derived defense peptides

Regarding the antibacterial mechanisms of these proteasome-derived defense peptides, Merbl's team also conducted research.

Based on transmission electron microscopy, they found that after treating bacteria with synthetic proteasome-derived defense peptides, the bacterial cell membranes became distorted and ruptured, releasing cytoplasmic contents.

This is consistent with previous studies on the mechanisms of action of antimicrobial peptides, where due to the presence of anionic phospholipids on the bacterial cell membrane, cationic peptides may disrupt the bacterial cell membrane through biophysical interactions.

▲ After treatment with proteasome-derived defense peptides, bacterial cell membranes become distorted and rupture (right)

It is worth noting that Merbl's team also discovered that infections promote the production of proteasome-derived defense peptides.

Within one hour after infection, the quantity of anti-infective peptides doubled compared to the uninfected control group. This phenomenon suggests that during the bacterial infection process, the proteasome has stronger capabilities to produce antimicrobial peptides.

The underlying molecular mechanism is that PSME3 expression is upregulated after infection and binds to the proteasome, enhancing the catalytic ability of the key active center of the proteasome, promoting the generation of antimicrobial peptides.

After analyzing the human genome data, Merbl's team found that at least one potential antimicrobial peptide with cationic termini exists in 92% of annotated genes, estimating that 270,872 potential proteasome-derived defense peptides can be generated.

▲ Schematic diagram of proteasome producing antimicrobial peptides [2]

In summary, Yifat Merbl's team's research findings reveal a new function of the "protein shredder" proteasome, discovering a previously unknown innate immune pathway, enriching our understanding of the immune system, and opening up new ideas for the development of infection-fighting drugs.

When faced with such research results, you can't help but marvel: evolution is truly great.

After all, who would have thought that almost all proteins in the human body carry antibacterial weapons?

In fact, in recent years, scientists have made many pioneering discoveries in the field of innate immunity, and we have also made systematic summaries in the "30 Lectures on Medical Trends." Interested friends can check it out.

Reference:

[1]. Goldberg K, Lobov A, Antonello P, et al. Cell-autonomous innate immunity by proteasome-derived defence peptides. Nature. Published online March 5, 2025. doi:10.1038/s41586-025-08615-w

[2]. Clausen T. Protein waste turned into antibiotics as a defence strategy of human cells. Nature. Published online March 5, 2025. doi:10.1038/d41586-025-00514-4

Author | BioTalker