Initiation and resolution of inflammation is essential for cellular homeostasis, and aberrations are often associated with disease. Following viral infection, initiation of an immune response requires addition of a small protein called ubiquitin to receptors that sense viral RNA, while addition of more ubiquitin molecules terminates the response. As a result, the enzymes that add ubiquitin have key roles in activating and restricting immune responses. Here we will study the ubiquitin ligase RNF125, which helps resolve immune responses. The proposed Project will use biochemical approaches to investigate how RNF125 regulates resolution of inflammatory responses by studying its role in turning off signaling by Rig-I, a key receptor of viral invasion. This work will provide fundamental knowledge about the mechanisms of inflammatory signalling, identify possible molecular targets for cancer and chronic inflammation, and explain how immunostimulatory therapies that are being developed to enhance cancer treatments might achieve maximum benefit.