Yersinia-induced deregulation of cellular life and death signals in macrophages

• Applicants: Professor Dr. Klaus Ruckdeschel; Professor Dr. Andreas Tholey
• Subject Area: Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 274839312

Death of host cells is a prominent characteristic in the crosstalk of a microbial pathogen with the host immune system. Quantity and mode of cell death have substantial impact on the host immune response and the outcome of infection. The pathways involved in the regulation of cell vitality and death during infection are, however, poorly understood. In our studies we use the gram-negative enteropathogenic bacterium Yersinia enterocolitica as tool to gain insights into the regulation of cell death-inducing and -preventing signals in bacteria-infected host immune cells. Yersinia suppresses central proinflammatory signaling pathways in infected cells and elicits apoptosis in macrophages. These events depend on a specific bacterial Yop virulence protein which modifies key host cell kinases by acetylating serine and threonine residues to block phosphorylation and activation of the kinases by upstream signals. Our studies indicate that the immunomodulatory activities of Yersinia also target the kinase Receptor-interacting protein-1 (RIP1) in infected macrophages. RIP1 is a master regulator of multiple cell fate decisions. It acts as a molecular switch between cell survival, death and inflammation. Yersinia modifies the phosphorylation pattern of RIP1 and engages RIP1 for apoptosis induction in macrophages. The molecular mechanisms by which Yersinia targets RIP1 and the physiological consequences thereof are, however, not yet defined. The current project aims to biochemically, molecularly and functionally characterize the posttranslational modifications induced by Yersinia on RIP1 (phosphorylation, acetylation) and to link the identified RIP1 modifications to biological responses. We expect from these studies basic new insights into the regulation of programmed cell death pathways in innate immune cells. Furthermore, since RIP1 is a central control element of cell vitality under multiple cellular stress conditions, the implications of this work could be of general importance for understanding death and life decisions in human biology and for intervention strategies in associated diseases.

• DFG Programme: Research Grants