'Trim-Away': Targeted Degradation of Proteins & Pathogens

Antibodies provide protective immunity against diverse pathogens and are one of the principle goals of vaccination. Until recently, all of the antibody functions we knew about operated extracellularly, suggesting that once pathogens infect a cell they are safe from antibodies. However, our discovery of the cytosolic Fc receptor TRIM21 has revealed a complex system of intracellular antibody immunity that allows antibodies to provide protection inside cells. In the proposed research, we will capitalize on this discovery and the toolbox of assays and reagents developed during my previous investigator award to understand how TRIM21 works to prevent infection by diverse viruses. A key goal is to understand how TRIM21 synthesises different ubiquitin chains to activate immunity and target pathogens for degradation. The insight we gain will drive the development of technologies such as Trim-Away that can remove proteins from living cells and could form the basis of future therapeutics.