GBP1

Researchers have identified a 'guard mechanism' for a protein which attacks microbes in infected cells, opening the possibility of new treatments for Toxoplasma, Chlamydia, Tuberculosis and even cancer. Researchers have identified a 'guard mechanism' for a protein which attacks microbes in infected cells, opening the possibility of new treatments for Toxoplasma, Chlamydia, Tuberculosis and even cancer. A study, led by the University of Birmingham and published today (5th October) in Science has discovered the lock and key 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 research has revealed how the attack protein is controlled through a process called phosphorylation, a process in which a phosphate group is added to a protein by enzymes called protein kinases. The kinase targeting GBP1 is called PIM1 and can also become activated during inflammation. Phosphorylated GBP1 in turn is bound to a scaffold protein, which keeps uninfected bystander cells safe from uncontrolled GBP1 membrane attack and cell death. The newly discovered mechanism prevents GBP1 from attacking cell membranes indiscriminately, creating a guard mechanism 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 Daniel Fisch said: "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, 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." Dr Frickel and her team conducted this initial research on Toxoplasma gondii, a single-celled parasite that is common in cats. Whilst Toxoplasma infections in Europe and Western countries are unlikely to cause serious illness, in South American countries it can cause reoccurring eye infections and blindness and is particularly dangerous for pregnant women. The researchers found that 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 GBP1 attacking Toxoplasma and removing the infected cells. Dr Frickel continued: "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." PIM1 is a key molecule in the survival of cancer cells, while GBP1 is activated by the inflammatory effect of cancer. The researchers think that by blocking the interaction between PIM1 and GBP1 they could specifically eliminate cancer cells. Dr Frickel said: "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."

A specific group of bacteria-killing proteins inside the immune system could hold the key to developing smarter and more effective drugs capable of eliminating certain infectious diseases including meningitis, pneumonia and sepsis, according to new research. A specific group of bacteria-killing proteins inside the immune system could hold the key to developing smarter and more effective drugs capable of eliminating certain infectious diseases including meningitis, pneumonia and sepsis, according to scientists from The Australian National University (ANU). In a new study published in Nature Communications, the ANU researchers demonstrate the potential of these immune proteins, known as guanylate-binding proteins (GBPs), to directly bind to and kill specific types of bacteria. In addition to laying the foundation for new treatments, these killer proteins can also be used in combination with existing antibiotics to give doctors more options when treating certain types of infectious diseases. Lead author and PhD scholar Shouya Feng, from The John Curtin School of Medical Research (JCSMR) said this specific type of protein works by "busting open" bacteria -- similar to an axe splitting wood in two -- destroying the membrane and causing it to die. "Our immune system is equipped with weapons that can destroy germs. When foreign bodies, such as bacteria, enter our body the immune system triggers a defensive response," Ms Feng said. "We believe we can extract and harness the power of these immune system proteins, known as GBP1, and use them to treat a range of infectious diseases, without negatively affecting our body's cells." Co-author Professor Si Ming Man, also from JCSMR, said disease-causing microbes are continually adapting to and outsmarting current drug treatments, and scientists are always looking to uncover new ways to develop more effective solutions. According to research carried out by the World Health Organization (WHO), drug-resistant diseases already cause about 700,000 deaths globally each year. By 2050, that figure is estimated to climb to 10 million. "The extensive use of antibiotics to treat a number of different infectious diseases over many years has made them less effective over time because microbes are continually developing resistance to new and existing treatments, meaning they're staying one step ahead of scientists," Professor Man said. "We are now finding more and more GBPs that can kill different types of drug-resistant bacteria. This includes bacteria that can cause meningitis, pneumonia and sepsis. "The ultimate goal is to use these proteins to eliminate meningitis, pneumonia and sepsis entirely. "Our research could provide alternatives to increasingly over-used and ineffective antibiotics by offering new methods to combat these multidrug-resistant infections. "We expect this work could lay the foundations for a new framework to inform how we can fight continually-evolving diseases for decades to come."