The impact of linear ubiquitination on the innate immune sensing of viral RNA (360G-Wellcome-203778_Z_16_A)

During a virus infection our cells are able to sense and respond to the invading pathogen and try to fight it off. The ability of our cells to directly detect the genomes of invading viruses is an essential part of this defence mechanism. Inside our cells, viral genomes are detected by specialised proteins called pattern recognition receptors (PRRs). These PRRs include retinoic-acid inducible gene I (RIG-I) and melanoma differentiation antigen 5 (MDA5), that can bind to the RNA of the viral genome and trigger potent anti-viral responses. We are interested to understand how activation of these PRRs can result in inflammation and cell death. We hypothesize that a particular protein modification, called linear ubiquitin, directs the immune response to RNA virus infection by determining the outcome of PRR activation. To explore this, we will study how linear ubiquitination alters the balance between cell death and gene activation resulting from of RIG-I and MDA5 activation, as well as explore the molecular mechanism(s) by which it regulates these signalling pathways. This will enable us to measure the contribution of linear ubiquitin to PRR signalling, showing a possible mechanism for regulating the immune response to drive effective immunity against viruses.