Protein ubiquitination is ubiquitous, as its name implies, and is emerging as a key regulator of protein homeostasis and cell signalling. Deregulation of protein ubiquitination is involved in a variety of human diseases, including cancer and neurodegenerative and inflammatory conditions. The last decade has revealed a plethora of distinct ubiquitin signals. 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.
Mass spectrometry has taken centre stage to access the complexity of ubiquitin signals. Tryptic digest of a ubiquitinated protein decorates ubiquitinated residues with a 114 Da GlyGly signature to aid site identification, however much of the complexity that originates from polyubiquitin architecture, or co-modifications, is being lost.
We recently reported Ub-clipping, a new methodology exploiting a viral leader protease that cleaves ubiquitin (and the ubiquitin-like modifier ISG15) from proteins while preserving the GlyGly modification on the intact protein (Swatek et al, Nature 2019). Ub-clipping enables new workflows, simplifies Ub site identification and offers unprecedented insights into the ubiquitin signals used in signalling pathways.