Human GBP1 controls pathogens and is regulated by the kinase PIM1 to ensure uninfected bystander cell survival
Professor Eva Frickel, University of Birmingham, UK, will be visiting us on Monday 2 December 2024 in the CMU.
Her talk, entitled "Human GBP1 controls pathogens and is regulated by the kinase PIM1 to ensure uninfected bystander cell survival" is scheduled at 11h15 in Auditoire Müller.
The speaker is hosted by Prof. Dominique Soldati and this seminar is organised by the Department of Microbiology and Molecular Medicine.
Biography
Professor Eva Frickel studied Chemistry and Biochemistry at the Universities of Freiburg (Germany) and Uppsala (Sweden) before pursuing a PhD at the ETH Zurich (Switzerland) under the guidance of Prof Ari Helenius. During her PhD, she researched enzymatic activities and interactions of protein-folding chaperones in the endoplasmic reticulum. Cellular protein folding and degradation machineries are important during antigen processing in immunity to infections. Thus she joined Prof Hidde Ploegh’s lab at Whitehead/MIT (USA) as a postdoc, employing novel chemical and technological approaches to work on immunity to the parasite Toxoplasma gondii. She identified CD8 T cell epitopes and developed murine models to study endogenous Toxoplasma-specific CD8 T cells. She also studied a novel class of enzymes, the murine guanylate binding proteins (GBPs) as players to open the compartment Toxoplasma resides in, the vacuole, giving antigens a route to immune presentation. In her own lab at NIMR/Crick in London (UK), Prof. Frickel continued to define CD8 antigen affinity and how it shapes T cell responses. Since 2016, she has focused on how immune-stimulated infected cells target intracellular pathogen vacuoles in general - during Toxoplasma and also bacterial infections. Her lab now exclusively studies human cells. She moved her lab to the University of Birmingham (UK) in 2020.
Read more: https://frickellab.com/contact/
Lecture summary
Bacterial and parasitic infections cause the production of the cytokine interferon-gamma (IFNy) which triggers broad anti-microbial activities active in macrophages, but also in non-immune cells. They have defined host response pathways in human IFNy-stimulated macrophages after infection with Toxoplasma gondii and Salmonella Typhimurium.
Both Toxoplasma and S. Typhimurium reside in vacuoles, so does this mean both are controlled by the same host intracellular pathways? A major player in executing macrophage host cell death after infection is the human IFNy-induced Guanylate Binding Protein 1 (GBP1). GBP1 targets these intracellular pathogens but drives the destruction of the Toxoplasma vacuole while binding S. Typhimurium directly after the bacteria escape their vacuoles. These differences result in divergent host cell death pathways.
While GBP1 limits microbial replication and coordinates host cell death in infected cells, how can its “aggressive” membrane-destroying capacity be controlled in uninfected cells? In studying GBP1 in uninfected cells, we have found that an IFNy-induced kinase, PIM1, phosphorylates GBP1 driving it towards its locked state bound to a cellular scaffold protein. PIM1 is an extremely short-lived protein. Pathogens such as Toxoplasma block IFNy signalling and thus inadvertently block PIM1 production leading to the release of GBP1 from its scaffold in infected cells. At the same time, GBP1 is safely stored in the locked state in uninfected cells. PIM1 is thus the guard of IFNy signalling. Immunity is driven by a secondary line of pathogen destruction unleashed when the pathogen disrupts the guard of the integrity of host immune pathways. This immune response falls under the newly coined paradigm of effector-triggered immunity.