Supervisors: Dr Gracjan Michlewski, Dr Sander Granneman
Project Description:
RNA viruses continue causing devastating epidemics and pandemics in the 21st century. For example, influenza A virus kills 250,000 to 500,000 people annually and generates huge socioeconomic burden1. The first line of defence against RNA viruses is the innate immune system. TRIM25 is a key factor in this process2. It enables innate immune response to RNA viruses by activating key host anti-viral pathways.
Using our expertise in RNA biology, we discovered that TRIM25 binds to RNA3. We hypothesise that during infection by RNA viruses, TRIM25 senses and restricts the virus by binding to specific viral RNAs. However, detailed characterisation of TRIM25/RNA interactions during viral infection is still missing.
The aim of this PhD is to take advantage of Michlewski’s and Granneman’s expertise in functional and bioinformatic characterization of RNA-protein complexes, respectively. The PhD student will use UV crosslinking and immunoprecipitation followed by high throughput RNA sequencing (CLIP-seq) to establish functionally important TRIM25 interactions with viral (influenza A) and host (human) RNAs. This will be followed by a series of cutting edge experiments to understand how these interactions contribute to TRIM25’s anti-viral role.
The outcome of this research will reveal how TRIM25 uses its RNA-binding activity for anti-viral functions and will provide a platform for the development of novel, RNA-based anti-viral therapeutics.
References:
1.Gasparini, R. et al. Clinical and socioeconomic impact of seasonal and pandemic influenza in adults and the elderly. Hum Vaccin Immunother 8, 21-8 (2012).
2.Meyerson, N.R. et al. Nuclear TRIM25 Specifically Targets Influenza Virus Ribonucleoproteins to Block the Onset of RNA Chain Elongation. Cell Host Microbe 22, 627-638 e7 (2017).
3.Choudhury, N.R. et al. RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC Biol 15, 105 (2017).
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