Viruses (and some bacteria and parasites) ply their trade inside our cells, where they access a resource-rich environment packed with the building blocks they require to copy and spread. Our cells produce an array of proteins that detect incoming and replicating pathogens. Some of these proteins trigger an alarm system, fine-tuned over hundreds of thousands of years, which suppresses viral replication. Our goal as a research team is to address the following questions:
Which proteins detect pathogens inside our cells?
Which features of infection are cells trained to detect?
How do antiviral proteins interrupt viral replication?
Can we manipulate these proteins to induce broad antiviral protection?
We integrate infection biology, molecular virology, biochemistry and chemical biology to study these systems. We employ a variety of viral (and some bacterial) infection models, allowing us to illuminate different aspects of this intracellular immune system.
Currently, we are working on an RNA-sensing enzyme called oligoadenylate synthetase 2 (OAS2), an unusual kind of template-independent RNA polymerase that generates a single-stranded nucleic acid comprising a string of adenosines linked by atypical 2′-5′ phosphodiester bonds. Another project in the lab is investigating the repression of HIV-1 transcription by a transcriptional repressor called TCF7L1.
A central focus of the lab is a group of enzymes called ubiquitin ligases (or E3s). E3s transfer a small protein called ubiquitin on to other molecules. With the advent of new technologies and ideas, it has come to light that not just proteins are labelled with ubiquitin, but lipids (fats), carbohydrates (sugars) and nucleotides can also become labelled. While protein ubiquitination has been studied for decades, the consequences of non-protein ubiquitination is still largely unknown. We are particularly interested in how this phenomenon relates to this intracellular innate immune system.
Our team experiments at the cutting edge of ubiquitin research with general aims to:
1) uncover novel E3 activities regulated by pathogen infection;
2) dissect the biochemistry and biology of these enzymes to understand how their behaviour is related to viral replication;
3) devise ways of exploiting these enzymes as research tools or therapeutic targets.
By understanding how antiviral E3s work, we aim to exploit their activity in new kinds of antimicrobial therapy.
One way that we identify E3s is to employ E3-specific activity-based probes. These tools were designed in the Virdee Lab in Dundee (see Collaborators) and are semi-synthetic proteins that selectively and covalently react with E3s in their active states. Read more about these tools in our Technology page.
The Fletcher Lab 