Researchers have found a guard mechanism for protein which attacks microbes in infected cells.
The University of Birmingham-led study has identified a guard mechanism that controls the attack protein GBP1. GBP1 is activated during inflammation and has the potential to attack membranes within cells and destroy them.
The lock and key mechanism found has opened the possibility for new treatments for Toxoplasma, Chlamydia, Tuberculosis and even cancer.
The study, ‘PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection,’ is published in the journal Science.
How does the protein guard mechanism work?
The research showed that the attack protein is controlled through a process called phosphorylation. This process involves a phosphate group being added to a protein by enzymes called protein kinases.
The kinase targeting GBP1 is called PIM1 and can also become activated during inflammation.
In turn, phosphorylated GBP1 is bound to a scaffold protein, keeping uninfected bystander cells safe from uncontrolled GBP1 membrane attack and cell death.
The guard mechanism prevents GBP1 from attacking cell membranes indiscriminately, creating a protective shield that is sensitive to disruption by the actions of pathogens inside the cells.
The new discovery was made by Daniel Fisch, a former PhD student in the Frickel lab working on the study.
Dr Eva Frickel, Senior Wellcome Trust Fellow at the University of Birmingham, who led the study explained: “This discovery is significant for several reasons. Firstly, guard mechanisms such as the one that controls GBP1 were known to exist in plant biology but less so in mammals. Think of it as a lock and key system. GBP1 wants to go out and attack cellular membranes, but PIM1 is the key, meaning GBP1 is locked safely away.
“The second reason is that this discovery could have multiple therapeutic applications. Now we know how GBP1 is controlled, we can explore ways to switch this function on and off at will, using it to kill pathogens.”
The initial research was conducted on Toxoplasma gondii
The research team first conducted their study on Toxoplasma gondii, a single-celled parasite that is common in cats.
In South American countries, Toxoplasma infections are particularly dangerous for pregnant women and can cause reoccurring eye infections and blindness.
The team discovered that Toxoplasma blocks inflammatory signalling within cells, preventing the production of PIM1. This means that the guard mechanism disappears, allowing GBP1 to attack the parasite.
Using an inhibitor to switch PIM1 off or manipulating the cell’s genome also resulted in GBP1 attacking Toxoplasma and removing the infected cells.
Dr Frickel stated: “This mechanism could also work on other pathogens, such as Chlamydia, Mycobacterium tuberculosis, and Staphylococcus all major disease-causing pathogens which are increasingly becoming more resistant to antibiotics.
“By controlling the guard mechanism, we could use the attack protein to eliminate the pathogens in the body.
“We have already begun looking at this opportunity to see if we are able to replicate what we saw in our Toxoplasma experiments. We are also incredibly excited about how this could be used to kill cancer cells.”
The implications for the research in cancer treatment
GBP1 is activated by the inflammatory effect of cancer, while PIM1 is a key molecule in the survival of cancer cells.
The team believe that blocking the interaction between PIM1 and GBP1 could eliminate cancer cells.
Dr Frickel concluded: “The implication for cancer treatment is huge. We think this guard mechanism is active in cancer cells, so the next step is to explore this and see if we can block the guard and selectively eliminate cancer cells.
“There is an inhibitor on the market which we used to disrupt PIM1 and GBP1 interaction. So, if this works, you could use this drug to unlock GBP1 and attack the cancer cells
“There is still a very long way to go, but the discovery of the PIM1 guard mechanism could be a massive first step in finding new ways to treat cancer and increasingly antibiotic-resistant pathogens.”
