Targeted Pathogen Degradation and its Synergy with Antiviral Immunity (360G-Wellcome-339878_Z_25_Z)

TRIM21 is an intracellular antibody receptor and E3 ubiquitin ligase that mediates the rapid degradation of antibody-bound pathogens, thereby preventing infection. By recognising antibodies, TRIM21 can target an exceptionally broad range of substrates, including viral capsids and proteopathic aggregates. This proposal seeks to elucidate the molecular mechanisms underlying TRIM21’s ability to degrade such diverse targets, determine how degradation synergises with the wider immune response against different viruses and develop degrader- based tools for studying host-pathogen biology. In Aim 1, we will determine how TRIM21 selects between proteasomal and autophagic degradation pathways, challenging the prevailing assumption that these systems operate independently. Aim 2 will investigate how TRIM21’s unique catalytic mechanism—substrate caging and proximity-induced activation—enables ubiquitination of structurally diverse molecules. Aim 3 will examine how degradation pathway choice influences TRIM21’s coordination with innate immune sensing and adaptive responses during infection in mouse models. Finally, Aim 4 will develop antibody-independent TRIM21-based degraders, including chimeric bioPROTACs and small-molecule ‘VIRTACs’, to explore targeted pathogen degradation as both a discovery tool and potential antiviral strategy. Together, these studies will define how TRIM21 orchestrates intracellular antibody immunity, reveal how degradation pathway selection shapes immune outcomes, and establish a foundation for TRIM21-inspired degraders.