Leo James - Medical Research Council Laboratory of Molecular Biology, UK

Leo James - Medical Research Council Laboratory of Molecular Biology, UK

Location: 
Seminar Room 1
Start Time: 
Fri, 15/02/2019 - 9:30am
End Time: 
Fri, 15/02/2019 - 10:30am

​Trim-Away: Targeted degradation of pathogens and proteins by the cytosolic antibody receptor TRIM21

Special seminar hosted by Associate Professor Seth Masters

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 initiates a programme of ubiquitination that 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, cGAS and the inflammasome and induce a potent antiviral state. 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 ubiquitination and inflammatory signalling is regulated and how we have repurposed its unique 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.
 
Leo received his PhD from Cambridge University in 2000 and post-doc’d with Prof Dan Tawfik and Sir Greg Winter, on antibody structure, function and evolution. In 2007, Leo established a lab at the LMB in Cambridge studying 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 uniquely cytosolically expressed. 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 also investigates HIV post-fusion biology; recent work includes identifying the HIV capsid interface used to recruit import cofactors and dynamic pores in the capsid that are essential for HIV infection.