Cell-autonomous innate immunity by proteasome-derived defence peptides, 2025, Merbl et al

[John Mac]

Abstract
For decades, antigen presentation on major histocompatibility complex class I for T cell-mediated immunity has been considered the primary function of proteasome-derived peptides1,2.

However, whether the products of proteasomal degradation play additional parts in mounting immune responses remains unknown. Antimicrobial peptides serve as a first line of defence against invading pathogens before the adaptive immune system responds. Although the protective function of antimicrobial peptides across numerous tissues is well established, the cellular mechanisms underlying their generation are not fully understood.

Here we uncover a role for proteasomes in the constitutive and bacterial-induced generation of defence peptides that impede bacterial growth both in vitro and in vivo by disrupting bacterial membranes.

In silico prediction of proteome-wide proteasomal cleavage identified hundreds of thousands of potential proteasome-derived defence peptides with cationic properties that may be generated en route to degradation to act as a first line of defence.

Furthermore, bacterial infection induces changes in proteasome composition and function, including PSME3 recruitment and increased tryptic-like cleavage, enhancing antimicrobial activity. Beyond providing mechanistic insights into the role of proteasomes in cell-autonomous innate immunity, our study suggests that proteasome-cleaved peptides may have previously overlooked functions downstream of degradation.

From a translational standpoint, identifying proteasome-derived defence peptides could provide an untapped source of natural antibiotics for biotechnological applications and therapeutic interventions in infectious diseases and immunocompromised conditions.

https://www.nature.com/articles/s41586-025-08615-w

 

[John Mac]

BBC article covering the study.

A new part of the immune system has been discovered and it is a goldmine of potential antibiotics, scientists have said.

They've shown a part of the body known to recycle proteins has a secret mode that can spew out an arsenal of bacteria-killing chemicals.

The researchers in Israel say it transforms our understanding of how we are protected against infection.

And gives a new place to look for antibiotics to tackle the growing problem of superbugs that resist our current drugs.

The discovery centres on the proteasome – a tiny structure that is found in every cell of the body.

Its main role is to chop up old proteins into smaller chunks so they can be recycled to make new ones.

But a series of experiments, detailed in the journal Nature, external, shows the proteasome detects when a cell has been infected by bacteria.

It then changes structure and role. It starts transforming old proteins into weapons that can rip open the outer layer of bacteria to kill them.

Prof Yifat Merbl, from the Weizmann Institute of Science, told me: "This is really exciting, because we never knew that this was happening.

"We discovered a novel mechanism of immunity that is allowing us to have a defence against bacterial infection.

"It's happening throughout our body in all the cells, and generates a whole new class of potential natural antibiotics."

The research team went through a process they called "dumpster diving" to find these natural antibiotics.

They were tested on bacteria growing in the laboratory and on mice with pneumonia and sepsis. The researchers said they were getting results comparable to some established antibiotics.

And when the researchers took cells in the laboratory and disabled the proteasome they were far easier to infect with bacteria like Salmonella.

Prof Daniel Davis, the head of life sciences and an immunologist at Imperial College London, said the findings were "extremely provocative and very interesting" as they changed our understanding of how our body fights infection.

"What's really exciting about this, is it's a totally undiscovered process by which anti-germ molecules are made inside our cells, it feels profoundly important and surprising."

But he cautioned that turning this into a new source of antibiotics is an idea that "still needs to be tested" and that will take time.

More than a million people a year are estimated to die from infections that are resistant to drugs like antibiotics.

But despite the need, there has been a lack of research into developing new antibiotics to keep up with demand.

Against that bleak background, having somewhere new to look is a source of optimism for some scientists.

Dr Lindsey Edwards, a senior lecturer in microbiology at King's College London, told the BBC: "It's a potential goldmine for new antibiotics, that's quite exciting.

"In previous years it's been digging up soil [to find new antibiotics], it is wild that it's something we have within us, but comes down to having the technology to be able to detect these things."

She also says there could be fewer issues with developing them into drugs because they are already products of the human body so the "safety side of it might be a lot easier".

https://www.bbc.co.uk/news/articles/cpv4jww3r4eo

 

[Utsikt]

I’ve learned to be hesitant about claims about groundbreaking discoveries. But if this is something completely new, maybe the root cause of ME also can lie in something that’s currently undiscovered?

 

[Kitty]

maybe the root cause of ME also can lie in something that’s currently undiscovered?

I think it probably does, which is why we haven't got very far.

Even if the whole BPS thing had never happened and all that money had gone into biomedical research, it's possible we still might not have found it. It might take a combination of new ideas plus a technology that wasn't always available.

 

[Yann04]

maybe the root cause of ME also can lie in something that’s currently undiscovered?

That’s always been my hunch. ME seems to fuck up the body pretty bad, but it’s pretty much impossible to see anything abnormal looking inside the body. I think we simply either don’t know where to look, or don’t really understand what we are looking at.

 

[Creekside]

This sort of discovery is also useful for when a doctor says "Your body can't be doing that." when you complain about something that they are not used to. The human body is just too complex for doctors to know what can't be happening in there.