Scientists have identified a regulatory function in the GBP1 protein, which is responsible for combating microbes within cells that have been infected. This seminal discovery has the potential to inform new treatment strategies for diseases such as Toxoplasma, Chlamydia, Tuberculosis, and cancer. The regulatory function operates akin to a “lock and key” system and holds promise for groundbreaking therapeutic applications.
The newly discovered protective feature in the attack protein could be harnessed to eliminate pathogens like Toxoplasma as well as cancerous cells.
Investigators have pinpointed a protective function for GBP1, a protein recognized for its ability to target microbes within cells that are infected. This groundbreaking revelation could serve as a foundation for the development of new therapeutic approaches against diseases like Toxoplasma, Chlamydia, Tuberculosis, and cancer.
The study, led by the University of Birmingham and published in the academic journal Science, reveals a “lock and key” system that governs the activity of the attack protein GBP1. This protein is activated during inflammatory responses and has the capacity to target and destroy intracellular membranes.
Regulatory Mechanism Explained
The study reveals that the activity of GBP1 is regulated via phosphorylation, a process that entails the addition of a phosphate group to the protein through the action of enzymes known as protein kinases. The kinase that targets GBP1 is PIM1, which is also activated during inflammatory responses. Once phosphorylated, GBP1 is linked to a scaffold protein, thus safeguarding uninfected cells from unregulated GBP1 activity, which could otherwise lead to cellular destruction.
This newly identified mechanism prevents GBP1 from indiscriminate activity against cell membranes, thereby serving as a protective function that can be disturbed by the presence of pathogens within cells. The revelation was credited to Daniel Fisch, a former doctoral student in the Frickel lab who participated in the study.
Dr. Daniel Fisch stated, “The project took six years to complete and involved collaborative efforts from multiple research organizations globally. Collaborators included The Francis Crick Institute in London, EMBL in Grenoble, France, ETH Zurich in Switzerland, and Osaka University in Japan.”
Implications and Future Directions
Dr. Eva Frickel, Senior Wellcome Trust Fellow at the University of Birmingham and leader of the study, commented: “The discovery is significant for multiple reasons. Regulatory mechanisms similar to this were previously known to exist in plant biology but were less studied in mammalian systems. The mechanism allows GBP1 to be securely stored, and PIM1 serves as the key to unlocking its activity.”
She further elaborated, “Understanding how GBP1 is regulated allows for the exploration of strategies to activate or deactivate this function, providing a potential means to eliminate pathogens.”
Initial experiments were conducted on Toxoplasma gondii, a unicellular parasite prevalent in cats. While in Europe and Western nations this parasite is generally not a serious health threat, in South American countries it can lead to recurrent eye infections, blindness, and is particularly hazardous for pregnant women.
Researchers discovered that Toxoplasma inhibits inflammatory signaling within cells, which blocks the production of PIM1 and thus deactivates the “lock and key” system, freeing GBP1 to target the parasite. Turning off PIM1 through an inhibitor or by altering the cellular genome also caused GBP1 to engage in anti-Toxoplasma activity.
Dr. Frickel further noted: “This mechanism could potentially be applied against other disease-causing pathogens like Chlamydia, Mycobacterium tuberculosis, and Staphylococcus, which are becoming increasingly antibiotic-resistant. Our team is currently exploring this avenue and is also excited about the potential applications for targeting cancer cells.”
PIM1 plays a crucial role in the survival of cancer cells. GBP1 is activated by the inflammation caused by cancer. By interrupting the interaction between PIM1 and GBP1, there is a potential for specifically targeting cancer cells.
Dr. Frickel concluded, “The implications for cancer therapy are considerable. The next step is to explore the possibility of inhibiting this protective function to selectively target and destroy cancer cells. There is an existing inhibitor that disrupts the interaction between PIM1 and GBP1, and if successful, this medication could be employed to activate GBP1 against cancer cells. Although a long journey still lies ahead, this discovery of the PIM1 protective function may be a monumental first step in identifying new avenues for treating cancer and antibiotic-resistant pathogens.”
The research was financially supported by the Wellcome Trust.
Reference: “PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection” authored by a global team of scientists, published in the journal Science on October 6, 2023. DOI: 10.1126/science.adg2253.
Frequently Asked Questions (FAQs) about GBP1 protein mechanism
What is the main discovery of the research led by the University of Birmingham?
The main discovery is the identification of a regulatory function in the GBP1 protein, which is known for its ability to target microbes in infected cells. This mechanism, likened to a “lock and key” system, could potentially offer groundbreaking therapeutic applications for diseases like Toxoplasma, Chlamydia, Tuberculosis, and cancer.
Who conducted the research and where was it published?
The research was led by the University of Birmingham and was published in the academic journal Science.
How does the “lock and key” mechanism work in GBP1 protein?
The “lock and key” mechanism in GBP1 works through phosphorylation. In this process, a phosphate group is added to GBP1 by an enzyme called PIM1. The phosphorylated GBP1 is then bound to a scaffold protein, effectively regulating its ability to attack intracellular membranes. This system safeguards uninfected cells from potential destruction.
What are the potential implications of this discovery for cancer treatment?
The discovery could have considerable implications for cancer treatment. PIM1 is vital for the survival of cancer cells, while GBP1 is activated by the inflammation caused by cancer. By disrupting the interaction between PIM1 and GBP1, there is a potential for specifically targeting and eliminating cancer cells.
How could this discovery affect the treatment of other diseases?
Besides cancer, this discovery could be pivotal in treating diseases that are becoming increasingly resistant to antibiotics, such as Chlamydia, Mycobacterium tuberculosis, and Staphylococcus. The regulation of GBP1 could be manipulated to target and eliminate these pathogens.
What is the next step in this line of research?
The next step is to explore the newly discovered mechanism further to understand its potential applications in treating diseases. This includes evaluating the possibility of inhibiting the protective function to selectively target and destroy cells, like those found in cancer and other diseases.
Who funded the research?
The research was financially supported by the Wellcome Trust.
Is the research collaborative, and if so, who are the collaborators?
Yes, the research was a collaborative effort involving multiple global research organizations, including The Francis Crick Institute in London, EMBL in Grenoble, France, ETH Zurich in Switzerland, and Osaka University in Japan.
More about GBP1 protein mechanism
- Original Research Paper in Science
- University of Birmingham Research News
- Wellcome Trust Funding Information
- The Francis Crick Institute
- EMBL Grenoble
- ETH Zurich
- Osaka University Research
- Information on GBP1 Protein
- General Information on Cancer Treatment
- Antibiotic Resistance