|Role of the ubiquitin-proteasome system (UPS) in proteolysis and antigen presentation.|
|Recognition of ubiquitylated proteins by deubiquitylating enzymes (DUBs).|
Professor of Biochemistry and Mass Spectrometry
Regulation of the lifespan of proteins is key for most biological processes and when altered, can often associate with progression of diseases. When proteins reach the end of their lifetime, most of them get modified by the attachment of ubiquitin, a small protein of 76 amino acids. This modification has been implicated not just in the elimination of damaged proteins, but also in physiological proteolytic control of processes such as transcription, signal transduction, and cell cycle transitions. So far, analysis has principally focused on ubiquitin (ub) attachment, with several hundred ub conjugating enzymes characterized to date. Much less is known about enzymes that remove ub from substrate proteins, yet around a hundred genes have been identified, sharing consensus motifs for deubiquitylating enzymes (DUBs). Such diversity is inconsistent with a simple recycling function and strongly suggests a range of specific (but currently largely undiscovered) biological functions. Members of the DUB family are already known to contribute to neoplastic transformation and are implicated in neurodegenerative diseases, making them attractive targets for drug design.
Ubiquitin and the immune system:
We intend to analyze a particular subset of the deubiquitylating enzyme family, containing an ovarian tumor domain (OTU). This conserved motif encodes for a potential cysteine protease, and is conserved throughout evolution. However, the function of this class of proteins is largely unknown. An approach based on a tandem affinity purification strategy will be established to determine protein interaction partners. A proteomics screen for protease substrate discovery will be established to identify substrates and provide entry points for genetic and biochemical analyses of their function. Our studies indicate a central role for OTUs, in particular OTUB1, in regulating cell invasion and morphology by modulating the stability of small GTPases. The impact of these molecular interactions are studied within the context of host-pathogen interactions and tumourigenesis.
Activity-Based Protein Profiling (ABPP) for Cellular Deubiquitinase (DUB) and Inhibitor Profiling at Deep and High-Throughput Levels.
Jones HBL. et al, (2023), Methods in molecular biology (Clifton, N.J.), 2591, 101 - 122
Integrative omics reveals subtle molecular perturbations following ischemic conditioning in a porcine kidney transplant model
O’Brien DP. et al, (2022), Clinical Proteomics, 19
Nilabh Shastri – Towards understanding classical and non-classical MHC-I antigen processing and presentation
Kessler BM., (2022), Cellular Immunology, 382, 104638 - 104638
Hermansky-Pudlak syndrome type 1 causes impaired anti-microbial immunity and inflammation due to dysregulated immunometabolism.
Cavounidis A. et al, (2022), Mucosal immunology
Structural Premise of Selective Deubiquitinase USP30 Inhibition by Small-Molecule Benzosulfonamides
O'Brien DP. et al, (2022)