Role of ubiquitination in regulating the NLRP3 inflammosome
The inflammasome is an essential protein complex within the innate immune system. It drives the production of the pro-inflammatory cytokine interleukin-1β (IL-1β) through caspase-1 dependent signalling pathway. The NOD-, LRR-, and Pyrin domain-containing 3 (NLRP3) inflammasome can detect a wide range of microbial or non-microbial stimuli, including PAMPs and DAMPs, and it has been associated with neurodegenerative disease (1). Understanding the regulation of the NLRP3 inflammasome is therefore emerging as a major therapeutic strategy for preventing neurodegeneration, memory loss and disease (2).
The main objective of my DPhil Project is to use chemoproteomics and ubiquitomics tools to identify key components of the ubiquitination system that regulate neuroinflammation. This will initially focus on a proteomics approach using mass spectrometry and ubiquitin-based active site probes to discover deubiquitylating enzymes (DUBs) involved in formation of the ‘inflammasome’. Once these proteins have been identified, genetic and functional studies will be performed in collaboration with the Oxford Drug Discovery Institute. This will utilize primary rodent cells and human cellular models derived from induced pluripotent stem cells (iPSC) to understand the role of these proteins in regulating microglial activation and neuro-inflammation.
1. Swanson, Karen V., Meng Deng, and Jenny P-Y. Ting. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nature Reviews Immunology, 2019
2. Heneka, MT., Róisín M. McManus, and Eicke Latz. Inflammasome signalling in brain function and neurodegenerative disease. Nature Reviews Neuroscience, 2018