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NLRP3 Inflammasome “DUBbed” by UCH-L1, affecting IL-1β production macrophages and microglia

Activation of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome complex involves association with ubiquitin C-terminal hydrolase 1 (UCH-L1). UCH-L1 chemical inhibition and deletion interfere with NLRP3 assembly and IL-1β production in macrophages and microglia.

NLRP3

Led by Prof. Benedikt Kessler (COI&CMD&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 under resting and activated conditions. Using complementary techniques, such as APEX2 PL-MS, AP-MS, and small interfering (siRNA) screening, they traced the time-resolved PPI 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 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.

These 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.

Overall, this research highlights the role of UCH-L1 in controlling the NLRP3 inflammasome, offering potential avenues for therapy in inflammatory diseases. 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), Dr. Ricardo A. Fernandes (COI), Dr. Iolanda Vendrell (CMD&COI), Dr. Edward Jenkins (Kennedy Institute of Rheumatology), and many more.

 

The full article can be found here.

https://www.cell.com/cell-reports/fulltext/S2211-1247(24)00480-7