Researchers discover guard mechanism for protein that attacks microbes, opening up new treatment possibilities

Scientists at the University of Birmingham, in collaboration with international research teams, have unveiled an intriguing breakthrough regarding a protein known as GBP1, which plays a pivotal role in combating various infections, including toxoplasma, chlamydia, tuberculosis, and potentially even cancer.

In their study published in Science, the researchers uncovered a sophisticated “guard mechanism” that regulates the actions of GBP1, preventing it from indiscriminately attacking cell membranes. This mechanism relies on a process called phosphorylation, where enzymes called protein kinases, specifically PIM1 in this case, add phosphate groups to GBP1. Once phosphorylated, GBP1 binds to a scaffold protein, safeguarding uninfected neighboring cells from its destructive potential.

This newly discovered control system ensures that GBP1 only targets infected cells, making it sensitive to disruptions caused by pathogens within those cells. The primary investigator, Dr. Daniel Fisch, expressed his excitement about the six-year project, highlighting the invaluable contributions of international research groups.

Dr. Eva Frickel, Senior Wellcome Trust Fellow at the University of Birmingham and the study’s leader, emphasized the significance of this discovery. She likened it to a lock and key system, where GBP1 represents the eager attacker, while PIM1 acts as the key, securely locking GBP1 away.

The implications of this finding extend beyond mere biological understanding; it holds promise for various therapeutic applications. With insights into how GBP1 is controlled, researchers can explore methods to manipulate this mechanism, effectively turning it on or off to combat pathogens.

The initial research focused on Toxoplasma gondii, a parasite often found in cats, which can be particularly harmful to pregnant women and South American populations. The study revealed that Toxoplasma disrupts inflammatory signaling within cells, inhibiting the production of PIM1, thus releasing GBP1 to attack and eliminate the parasite. Inhibiting PIM1 or altering the cell’s genome in a way that turns it “off” also resulted in GBP1 attacking Toxoplasma-infected cells.

Dr. Frickel believes that this mechanism could be effective against other pathogens such as Chlamydia, Mycobacterium tuberculosis, and Staphylococcus, which are increasingly resistant to antibiotics. By controlling the guard mechanism, researchers could harness GBP1’s attack potential to eliminate these pathogens within the body.

Notably, PIM1 is a crucial molecule for cancer cell survival, and GBP1 is activated in response to cancer-related inflammation. Researchers are now exploring the possibility of blocking the interaction between PIM1 and GBP1 to specifically target and eliminate cancer cells. While this potential cancer treatment is still in its early stages, the discovery of the PIM1 guard mechanism represents a promising first step toward finding novel ways to combat cancer and antibiotic-resistant pathogens.

Source: University of Birmingham

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