Regulation of immune signalling via ubiquitin-mediated receptor degradation

Ubiquitin is a small protein used as a signpost for cell signalling events, thus regulating immune function and inflammation. Aberrant control of these processes contributes to autoimmune disorders such as scleroderma, lupus and rheumatoid arthritis. We published that removal of ubiquitin from immune receptors by the BRISC deubiquitylase is required for inflammatory signalling. In work leading up to this proposal, we identified new BRISC interactors that suggest BRISC regulates multiple receptors and pathways. Exactly how BRISC regulates these different receptors and signalling pathways is unknown. We generated first-in-class small molecule chemical BRISC inhibitors that we will use as probes to study BRISC function. Our multidisciplinary approach spanning structural, chemical and cellular biology will delineate how metabolic and ubiquitin-processing enzymes regulate immune signalling. These studies will transform our knowledge of immune regulation and uncover potential new therapeutic targets to treat autoimmune diseases.