The Fletcher Group
Cells are rigged with devices to prevent viral replication and the proteins that perform these functions are determinants of viral transmission. Identifying and understanding these proteins – and how they integrate into a collective cellular response – reveals core principles of antiviral immunity and offers a framework for the development of new kinds of antiviral therapy.
Intriguingly, some antiviral proteins are synthesised in response to infection, while others are present ‘at rest’ until a virus arrives. The latter cohort is difficult to study because its members are invisible to techniques that measure protein abundance gradients. We seek to illuminate this group because its members likely exhibit new kinds of antiviral mechanisms whose dynamic regulation might inspire new ideas for therapies.
Primarily, our group focuses on a class of enzyme called an E3 ubiquitin ligase (E3). E3s regulate all cellular processes by attaching a small protein called ubiquitin to other proteins, altering their behaviour or forming ‘messages’ that are transmitted through the cell. Several E3s have known roles in antiviral immunity, suggesting other members of this family of enzymes might also harbour cryptic antiviral behaviour. Moreover, so pervasive is ubiquitin that monitoring E3s during infection provides a panorama of cell-virus interactions.
Viruses also use ubiquitin to complete key stages of their lifecycles, like cell egress. Some viruses, including lentiviruses like HIV, sabotage cellular immunity by rewiring host E3s, turning the host on itself to degrade antiviral proteins. Others, like poxviruses, herpesviruses and coronaviruses, encode their own E3s or even ubiquitin ‘erasers’, which they use to disarm the host. Thus, by various means viruses have become fluent in the ubiquitin language and this contributes to their evolutionary success. We focus on coronaviruses and herpesviruses as models to understand how viruses employ or evade ubiquitin. This will provide fundamental insight into innate immunity and signpost toward antiviral development.
Research group members
Dr Alfredo Castello
Dr Sam Wilson
Dr Chris Boutell
Dr Ben Brennan
Prof Massimo Palmarini
Prof Greg Towers (University College London)
Dr Leo James (MRC-LMB)
Prof Satpal Virdee (MRC-PPU, University of Dundee)
Dr Eleanor Gaunt (The Roslin Institute, University of Edinburgh)
UKRI Future Leaders Fellowship (2021-2025)