Tipping the balance: higher-order assemblies and phase transitions in immune signal transduction

• Applicant: Dr. Theresia Gutmann
• Subject Area: Cell Biology ; Biochemistry
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 471561953

How do cells decide whether to initiate an immune response while permanently exposed to potential danger signals? Innate immunity sensors examine their immediate environment and detect a broad spectrum of molecular patterns. The discrimination between "benign" and "harmful" is a grand challenge for decision making. This problem is particularly apparent in the case of nucleic acid detection in the cytosol of mammalian cells. DNA is normally confined to nuclei or mitochodria, and its presence in the cytosol may indicate an infection or a disease state of the cell. Nucleic acid sensors function largely non-specifically, i.e., independently of the nucleotide sequence, which carries the risk of self-recognition and aberrant activation. Their activation induces inflammatory processes or various forms of cell death. The intrinsically non-specific but potent nucleic acid sensor activity must therefore be kept in check to avoid immunopathalogies. An important aspect of the coordination and robustness of cell signalling is the regulation of sensor sensitivity, signal strength and duration, which can be achieved by the spatial organisation of molecules. The aim of this project is to investigate the role of of the spatial organization of nucleic acid sensors and their compartmentalisation in condensates. Higher-order assemblies of nucleic acids and their sensors feature elevated local concentrations of signaling molecules, which alters biochemical rates and might tune signaling. I will use biochemical and biophysical in vitro reconstitution methods complemented with cell-based approaches to study the requirements for the formation of higher-order assemblies of innate immune sensors with nucleic acids. The emerging material properties of these compartments, the prerequisite for phase transitions and their dynamics will be described quantitatively and correlated with sensor activity. This project aims thus to contribute to the molecular understanding of specificity and robustness in immune signalling.

• DFG Programme: WBP Position