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A Cell Reports study led by Prof. Benedikt Kessler provides an intricate time-resolved molecular map of different phases of NLRP3 inflammasome activation and unveils ubiquitin C-terminal hydrolase 1 (UCH-L1) as a modulator of NLRP3 inflammasome assembly and IL-1β production.


Led by Prof. Benedikt Kessler (Principal investigator with CAMS Oxford Institute (COI), Centre for Medicines Discovery (CMD) & Target Discovery Institute(TDI)), Dr. Zhu Liang (COI, CMD & TDI) and Dr. Andreas Damianou (COI, CMD & TDI), a group of researchers employed APEX2 proximity labelling coupled with mass spectrometry to map the NLRP3 proximal proteome (entire complement of proteins expressed) under resting and activated conditions. Activation of the NLRP3 inflammasome complex is an essential innate immune signaling mechanism. APEX2 labelling allows identification and isolation of endogenous proteins. 

Using complementary techniques, such as APEX2 PL-MS, AP-MS, and small interfering (siRNA) screening, they traced the time-resolved protein-protein interaction networks local to the NLRP3 inflammasome upon stimulation. This approach offers a resource-rich map for further investigations of the molecular intricacies of NLRP3 inflammasome activation and revealed that ubiquitin C-terminal hydrolase 1 (UCH-L1) is involved in regulating IL-1β production.

Further experiments in both a reconstituted system and macrophages demonstrate that UCH-L1 interacts with the NACHT domain of NLRP3 and thereby interferes with ASC and NLRP3 assembly. Furthermore, UCH-L1 knockdown or chemical inhibition interferes with IL-1β production, particularly in microglia cells that exhibited elevated UCH-L1 expression as compared to peripheral monocytes or macrophages. The authors propose that UCH-L1 may play a "gatekeeper" role in NLRP3 inflammasome assembly, potentially through modulating ubiquitination of NLRP3.

Overall, this research highlights the role of UCH-L1 in controlling the NLRP3 inflammasome, offering potential avenues for therapy in inflammatory diseases. The findings suggest that pharmacological inhibition of UCH-L1 could be a promising therapeutic strategy for neuroinflammatory diseases involving aberrant NLRP3 activation. This is consistent with previous research linking UCH-L1 to various neurological disorders, including Parkinson's disease and Alzheimer's disease. 

The project involved a collaborative effort with scientists from various institutions, including Dr. Elena Di Daniel (Astex Pharmaceuticals), Prof. Edward W. Tate (Imperial College London), Prof. Tao Dong (COI & MRC TIDU), Dr. Ricardo A. Fernandes (COI), Dr. Iolanda Vendrell (COI & CMD), Dr. Edward Jenkins (Kennedy Institute of Rheumatology), and many more.


The full article can be found here.