Prof Jan Rehwinkel; University of Oxford
Current Position: Since 2012 Group leader, MRC Translational Immune Discovery Unit, Weatherall Institute of Molecular Medicine, University of Oxford, UK Research Experience: 2007-2012 Postdoctoral Research Fellow with Dr Caetano Reis e Sousa, Immunobiology Laboratory, Cancer Research UK, London Research Institute, London, UK 2003-2007 Doctoral Training with Dr Elisa Izaurralde, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany Qualifications: 2007 PhD, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany 2003 Diploma in Biology, Ruprecht-Karls University, Heidelberg, Germany (equivalent to MScdegree)
The innate immune response is critical for host defence against viruses. Cell-intrinsic mechanisms detect virus presence and restrict virus replication. Nucleic acids are often a molecular signature of infection and are recognised by receptors including Toll-like receptors, RIG-I-like receptors and cytosolic DNA sensors. These receptors signal for the induction of innate response genes such as those encoding type I interferons. These then induce the expression of restriction factors, host proteins that limit virus replication. Our work focuses on cytosolic nucleic acid sensors, in particular RIG-I, MDA5 and cGAS. We use in vitro and in vivo models of virus infections and are interested in rare genetic diseases linked to chronic anti-viral innate immune responses. In this presentation, I will discuss our recent work on MDA5, an innate immune RNA sensor that senses infection with a range of viruses and other pathogens. MDA5’s RNA agonists are not well defined. We used single-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) to study its ligands. Surprisingly, upon infection with SARS-CoV-2 or encephalomyocarditis virus, MDA5 bound overwhelmingly to cellular RNAs. Many binding sites were intronic and proximal to Alu elements and to potentially base-paired structures. Concomitantly, cytoplasmic levels of intron-containing unspliced transcripts increased in infected cells and displayed enrichment of MDA5 iCLIP peaks. Moreover, overexpression of a splicing factor abrogated MDA5 activation. Finally, when depleted of viral sequences, RNA extracted from infected cells still stimulated MDA5. Taken together, MDA5 surveys RNA processing fidelity and detects infections by sensing perturbations of posttranscriptional events such as splicing, establishing a paradigm of innate immune ‘guarding’ for RNA sensors.
Event Time & Dates
Event Details