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

We wish to determine how the cytosolic antibody receptor and E3 ligase TRIM21 uses its potent antiviral and immune signaling activity to prevent infection by diverse viruses. We will use our newly developed protein deletion technology 'Trim-Away' to determine the ubiquitin machinery necessary to synthesize the diverse ubiquitin chain types that allow TRIM21 to drive proteasomal degradation of viruses and trigger innate immunity. We will build on our structural studies of TRIM21 to define the mechanism by which its pro-inflammatory signaling is regulated and how other ligases and deubiquitinases are recruited. We will exploit our recent discovery that TRIM21 promotes antigen presentation, by investigating its role in targeting antigens for proteasomal degradation and stimulating protective T cell responses during LCMV, Influenza and SARS-CoV-2 infection. Together this work will define new roles for TRIM21 in host immunity and decipher how TRIM21 uses ubiquitin to provide antiviral protection. The insight we learn from these natural mechanisms will further the development of new technologies like Trim-Away and may inform future antiviral and vaccine development.