Health UK (Commonwealth Union) – A recent study, led by the University of Birmingham and published in Science, has unveiled a crucial “guard mechanism” governing a protein responsible for combating microbes within infected cells. This discovery opens the door to potential novel treatments for conditions such as Toxoplasma, Chlamydia, Tuberculosis, and even cancer.
The research sheds light on the regulatory mechanism that governs the attack protein GPB1, which becomes active during inflammatory processes and possesses the ability to target and disrupt cell membranes from within.
The study has elucidated the control of this attack protein through a process called phosphorylation, wherein enzymes known as protein kinases add phosphate groups to proteins. PIM1, a kinase activated during inflammation, targets GBP1, leading to its phosphorylation. Phosphorylated GBP1 then binds to a scaffold protein, safeguarding uninfected bystander cells against uncontrolled GPB1 membrane attacks and cell death.
This newly uncovered mechanism prevents GPB1 from indiscriminately attacking cell membranes, establishing a sensitive guard mechanism that can be disrupted by the activities of pathogens within the cells. The key contributor to this breakthrough was Daniel Fisch, a former PhD student in the Frickel lab who was dedicated to this remarkable project.
Dr. Daniel Fisch expressed his enthusiasm, indicating that this was a fantastic project to work on for the past six years and involved many research groups from all over the world. None of this would have been possible without help from our colleagues and friends at The Francis Crick Institute in London, EMBL in Grenoble (France), ETH Zurich (Switzerland), and Osaka University (Japan).
Dr Eva Frickel, Senior Wellcome Trust Fellow at the University of Birmingham, the lead of the study says “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 initiated their research by focusing on Toxoplasma gondii, a single-celled parasite commonly found in cats. While Toxoplasma infections in Europe and Western countries typically do not lead to severe illness, they can result in recurring eye infections and blindness in South American countries, posing a particular threat to pregnant women.
The researchers uncovered that Toxoplasma employs a strategy to inhibit inflammatory signaling within cells, preventing the production of PIM1. This disruption effectively dismantles the “lock and key” system, enabling GBP1 to target and combat the parasite. Turning off PIM1 through the use of an inhibitor or by manipulating the cell’s genetic makeup also led to GPB1 attacking Toxoplasma and eliminating the infected cells.
Dr. Frickel further indicated that, this mechanism holds promise for potential applications against other pathogens like Chlamydia, Mycobacterium tuberculosis, and Staphylococcus, all of which are major disease-causing agents increasingly developing antibiotic resistance. By regulating this protective mechanism, they could harness the attack protein to eradicate these pathogens within the body. They have already embarked on exploring this avenue to replicate the results we observed in our Toxoplasma experiments. Additionally, they are enthusiastic about its potential in targeting and destroying cancer cells.
PIM1 plays a crucial role in the survival of cancer cells, and GPB1 is activated by the inflammatory response triggered by cancer. The researchers believe that by disrupting the interaction between PIM1 and GPB1, they could selectively eliminate cancer cells.
