Regulation of immune signalling via ubiquitin-mediated receptor degradation

Immune receptor turnover and subcellular localisation are regulated by attachment of ubiquitin, which controls receptor internalisation and endosomal-lysosomal degradation. Receptor ubiquitylation is fine-tuned by ubiquitin-processing enzymes, ligands and adaptor proteins, which regulate immune signalling output in a spatio-temporal manner. We identified a new signalling complex called BRISC, which is a deubiquitylase (DUB) and required for recycling of interferon and Toll-like receptors (TLRs). BRISC partners with adaptor proteins SHMT2 and EPS15 to regulate interferon and TLR signalling, although the role for each adaptor is unclear. My laboratory uncovered a fascinating molecular mechanism by which vitamin B6 regulates BRISC activity, thus revealing a new example of metabolic control of immune signalling. Here, we aim to uncover how BRISC activity is controlled and directed to immune receptors. Using an integrated structural biology approach we aim to understand how BRISC partners with new adaptor proteins to perform its functions. Using BRISC-selective chemical probes in cell-based assays we aim to ascertain BRISC’s role in elevated inflammation in normal and disease conditions. These new tool compounds represent an exciting opportunity to better understand BRISC activity, receptor degradation and immune signalling functions, and how DUBs can be exploited as therapeutic targets for autoimmune diseases.