Intracellular antibody immunity and the targeted degradation of pathogens

Antibodies neutralize viruses by inhibiting their entry into cells but a fraction of antibody-bound pathogens still escape into the cytosol. To counter this, every cell expresses TRIM21, a dedicated cytosolic antibody receptor and E3 ligase. TRIM21 intercepts incoming antibody-bound pathogens and targets them for ubiquitin-dependent degradation. Pathogens represent extremely challenging substrates yet TRIM21 is capable of eliminating them quickly before replication begins. TRIM21 contributes to immune protection against a remarkably broad range of pathogens, including enveloped and non-enveloped viruses and intracellular bacteria. In my talk I will discuss what we are learning about the different mechanisms TRIM21 uses against diverse pathogens and how TRIM21 synergises with the wider immune response. We are also attempting to apply our learnings to the development of new technologies and therapeutics. In the technology “Trim-Away”, TRIM21 provides an alternative to siRNA or CRISPR to remove specific proteins from the cell, whilst small molecule degraders that use TRIM21 - ‘TRIMTACs’ – offer the possibility of a new antiviral modality.