The discovery of a ‘guard mechanism’ for a protein that attacks microbes in infected cells could pave the way for new treatments for infectious diseases and even cancer, British scientists say.
A study, led by the University of Birmingham, UK, revealed the ‘lock and key’ mechanism that controls the attack protein GPB1, which is activated during inflammation and has the potential to attack membranes within cells and destroy them.
The research, published in Science, has revealed how the attack protein is controlled through phosphorylation. The PIM1 kinase targets GBP1 and can also become activated during inflammation. In turn, phosphorylated GBP1 is bound to a scaffold protein, which keeps uninfected bystander cells safe from uncontrolled GBP1 membrane attack and cell death.
Dr Daniel Fisch, a former PhD student in the Frickel lab working on the study, found the newly discovered mechanism prevents GPB1 from attacking cell membranes indiscriminately, creating a guard mechanism that is sensitive to disruption by the actions of pathogens inside the cells.
Study leader Dr Eva Frickel, Senior Wellcome Trust Fellow at the University of Birmingham, said: “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. GPB1 wants to go out and attack cellular membranes, but PIM1 is the key meaning GPB1 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.”
Dr Frickel and her team conducted the initial research on Toxoplasma gondii, a single-celled parasite that is common in cats and in South American countries can cause in humans reoccurring eye infections and blindness and is particularly dangerous for pregnant women.
They found Toxoplasma blocks inflammatory signalling within cells, preventing PIM1 from being produced, meaning that the “lock and key” system disappears, liberating GBP1 to attack the parasite. Switching PIM1 ‘off’ with an inhibitor or by manipulating the cell’s genome also resulted in GPB1 attacking Toxoplasma and removing the infected cells.
“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,” she said.
“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.”
Fisch D, Pfleiderer MM, Anastasakou E et al. PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection. Science. 5 October 2023; doi: 10.1126/science.adg2253
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