Protein ubiquitination, as its name implies, is ubiquitous, and is emerging as a major regulator of protein homeostasis and cell signalling. Deregulation of protein ubiquitination is involved in a variety of human diseases, including cancer, inflammation and neurodegeneration. The last decade has shown that a plethora of distinct ubiquitin signals exist. My lab tries to understand the complex ‘ubiquitin code’ by focussing on the different ubiquitin signals themselves, in order to eventually link the specificity in the system back to physiological functions.
Deubiquitinases are emerging as key players in the regulation of the ubiquitin code. They hold huge therapeutic potential for their role in stabilising proteins – inhibiting the DUB that stabilises an oncogene should destabilise the oncogene. While we understand DUBs structurally and mechanistically in great detail, a complete picture of biological roles for DUBs is largely missing.
In my seminar, I will discuss our latest work on DUBs, focussing on the important inflammatory regulator OTULIN, its roles in disease and emerging roles in trafficking. OTULIN regulates exclusively a lowly abundant ubiquitin chain type, Met1-linked or ‘linear’ ubiquitin chains, and its involvement in new biological pathways suggests unappreciated roles for linear chains outside inflammation. Secondly, I will discuss two closely related USP deubiquitinases, USP25 and USP28. The latter stabilises the key-oncogene c-myc, and holds some promise as a drug target. Our structures of USP25 and USP28 indeed reveal a route to inhibition due to mechanisms of oligomerisation that regulate activity. Characterisation of adaptor regions in USP25 may indicate new biological functions that require careful follow-up studies.