Leo received his Ph.D. from Cambridge University in 2000, where he worked on antibody structure and design including the first humanised antibody CAMPATH. He post-doc’d in the labs of Prof. Dan Tawfik and Sir Greg Winter, investigating molecular mechanisms of antibody pathogenicity. In 2007, Leo established an independent group at the Laboratory of Molecular Biology in Cambridge. His lab studies intracellular host-pathogen interactions using a broad range of in vitro and in vivo techniques. In 2010, Leo discovered TRIM21, the most conserved and highest affinity antibody receptor in mammals and unique for its cytosolic expression. Since then, his lab has shown that TRIM21 prevents infection by intercepting viruses, bacteria and pathogenic proteins inside the cell and targeting them for rapid degradation. This work has also led to the development of ‘TrimAway’, a technique which exploits TRIM21 for the rapid and specific degradation of cellular proteins. Leo’s lab is now working to define the molecular mechanisms that underpin TRIM21 activity to further develop this technology and understand how intracellular antibody immunity is regulated. Leo also investigates HIV post-fusion biology; recent work includes identifying the HIV capsid interface used to recruit cofactors for nuclear import and discovering dynamic pores in the capsid that are essential for HIV infection.
TRIM21 is a recently discovered mammalian Fc receptor and E3 ubiquitin ligase expressed in the cytosol of all cells. The highest affinity IgG receptor in man, it mediates an intracellular humoral response against antibody-opsonized pathogens that invade the cytosol during infection. Upon detection, TRIM21 activates key immune transcription pathways to induce a potent antiviral state. Simultaneous with, and independent of, immune activation, TRIM21 recruits cellular degradation machinery, which catalyse the disassembly and destruction of cytosolic virions to prevent their replication. This rapid virion destruction also exposes the genomes of RNA and DNA viruses, allowing TRIM21 to potentiate the activity of RIG-I and cGAS to promote a rapid antiviral response. TRIM21 is effective against diverse viruses but also bacteria and proteopathic agents like tau. In my talk I will summarize key aspects of TRIM21 biology and focus on recent work showing how its inflammatory signaling is regulated and how we have repurposed its activity to perform targeted protein depletion. This latter technology, called ‘Trim-Away’, uses off-the-shelf antibodies to rapidly and acutely degrade cellular proteins in diverse cells.
This work was funded by the Medical Research Council (UK U105181010), European Research Council (IAI 281627) and the Wellcome Trust (Investigator Award).