Ubiquitin is a small protein that marks substrates for proteasomal degradation and can also alter protein function through post-translational modification. Ubiquitin conjugation to substrate proteins (aka ubiquitylation) is carried out by the sequential action of three enzymes, E1, E2, and E3, which together with the proteasome form the core of the ubiquitin-proteasome system (UPS). E3 ligases act as specificity modules, recruiting individual protein substrates for ubiquitylation and thereby ensuring timely and accurate removal of proteins that are no longer needed or whose structure and function have been compromised. Given this central regulatory role, targeting components of the UPS has become an area of intense interest in drug discovery and development.

Graphical abstract Prenyl UPS_edited.jpg

Protein degradation by the ubiquitin-proteasome system is well studied in the cytosol and nucleus, yet the precise mechanisms governing protein turnover at cellular membranes remain poorly understood, despite membranes being home to many of the most important and challenging targets in human disease, including receptors, transporters, and signaling kinases that drive cancer, neurological disorders, cardiovascular disease, and metabolic pathology.

Using unbiased, interdisciplinary approaches spanning cell biology, integrative structural biology, proteomics, and in vivo models, we have identified novel membrane-localized E3 ubiquitin ligases and are actively mapping the broader landscape of ubiquitin-proteasome machinery operating at cellular membranes, with the goal of defining how dysregulation of these pathways contributes to human disease.

Building on these discoveries, we are developing new strategies that complement conventional TPD platforms. Our goal is to establish a new, broadly applicable framework for protein degradation, with direct translational potential across oncology and beyond.