The sensor protein NLRP3 forms a multiprotein complex called the inflammasome in response to a wide range of stimuli, including microbes, amyloids, and asbestos fibers. It is one of the key mediators of inflammation in common diseases such as diabetes, cardiovascular disorders, neurodegenerative diseases, and cancer. For years, research groups have been trying to explain how NLRP3 can respond to such a broad spectrum of triggers. It was hypothesized that changes in specific cellular organelles, where the inflammasome is assembled, play an important role in this process.
Researchers from the National Institute of Chemistry, in collaboration with the Faculty of Medicine at the University of Ljubljana and the Institute of Structural Biology at the University of Bonn, took an innovative approach by directing NLRP3, normally located in the cytosol, to specific organelles. They demonstrated that neither the location nor the type of organelle is crucial, as diverse activators triggered inflammation even with organelle-restricted NLRP3 variants. However, it is essential for NLRP3 to bind a scaffold, not necessarily a membrane but also larger protein assemblies. The study suggests, that NLRP3 detects cellular changesinduced by various activators. Clustering of NLRP3 on such altered cellular scaffolds leads to the loosening of its inactive form, thereby enabling inflammasome formation. They showed that NLRP3 activation can be inhibited even at an intermediate step in its assembly, which is important for developing inhibitorsthat target excessive NLRP3 activation, often associated with chronic inflammatory diseases. By identifying a universal mechanism of activation, the study deepens our understanding of one of the most complex mediators of inflammation.
Authors of the study published in Nature Communications are Elvira Boršić, Taja Železnik Ramuta, Sara Orehek, Mateja Erdani Kreft, Matthias Geyer, Roman Jerala and Iva Hafner Bratkovič.
Graphical abstract
NLRP3 transitions from an inactive state to an active inflammasome by clustering on cellular scaffolds, a process triggered by diverse activators. Clustering rather than a specific subcellular location is key to inflammasome activation.
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