Ubiquitin modulators of immune signalling Professor Benedikt Kessler (University of Oxford) presents his work on ubiquitin and protease biology. Hosted by Dr Adam Dowle.
Event details
Abstract
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. Much less is known about enzymes that remove ubiquitin from substrate proteins, referred to as deubiquitylating enzymes (DUBs). Members of the DUB family are already known to contribute to neoplastic transformation and are implicated in immunity and neurodegenerative diseases, making them attractive targets for drug design. Our studies revealed that one of these DUBs, ubiquitin C-terminal hydrolase 1 (UCH-L1), interacts with the NACHT domain of NLRP3, a component of the inflammasome complex. Downregulation of UCH-L1 decreases pro-interleukin-1β (IL-1β) levels. UCH-L1 chemical inhibition with small molecules interfered with NLRP3 puncta formation and ASC oligomerization, leading to altered IL-1β cleavage and secretion, particularly in microglia cells, which exhibited elevated UCH-L1 expression as compared to monocytes / macrophages. Altogether, we profiled NLRP3 inflammasome activation dynamics and highlight UCH-L1 as an important modulator of NLRP3-mediated IL-1β production, suggesting that a pharmacological inhibitor of UCH-L1 may decrease inflammation-associated pathologies.
About the speaker
Professor Benedikt Kessler
Benedikt is a Professor of Biochemistry and Mass Spectrometry at the Target Discovery Institute, University of Oxford. Kessler graduated from the Swiss Federal Institute of Technology ETH in Zurich, Switzerland in biochemistry in 1992. He received his PhD in immunology at the Ludwig Institute for Cancer Research at the University of Lausanne, Switzerland in 1998. He then joined the laboratory of Hidde L. Ploegh at the Pathology Department at Harvard Medical School in Boston, USA, to study the role of proteolysis in MHC I antigen processing and presentation. After three years, he established a research platform in proteomics at Harvard Medical School. Currently he is Professor of Biochemistry and Life Science Mass Spectrometry at the Target Discovery Institute (TDI), Centre of Medicines Discovery, Department of Medicine, University of Oxford, UK. His laboratory is focused on ubiquitin and protease biology with a specialty in mass spectrometry, proteomics and recently in metabolomics. Expertise in his laboratory is also used to define “molecular signatures” in disease processes and accelerate target discovery in translational research.