Vall d'Hebron Talks by VHIR 'Understanding the activation mechanism of the NLRP3 inflammasome'

Speaker: Dr. Pablo Pelegrín, Scientific Deputy Director & Principal Investigator, BioMedical Research Institute of Murcia - Department of Biochemistry and Molecular Biology B and Immunology-Faculty of Medicine-University of Murcia

The NLRP3 inflammasome is activated in response to a wide range of stimuli and drives diverse inflammatory diseases. The decrease of intracellular K+ concentration is a minimal upstream signal to most of the different NLRP3 activation models. Here we found that cellular K+ efflux induces a stable structural change in the inactive NLRP3 promoting an open conformation as a step preceding activation. This conformational change is facilitated by the presence of the specific NLRP3 FISNA domain and a unique flexible linker sequence between the PYD and FISNA domains. This linker is also important to facilitate the ensemble of NLRP3PYD into a seed structure for ASC oligomerization. The introduction of the NLRP3 PYD-linker-FISNA sequence into NLRP6 resulted in a chimeric receptor able to be activated by K+ efflux-specific NLRP3 activators and promoted an in vivo inflammatory response to uric acid crystals. Our results establish that the N-terminal sequence between PYD and NACHT domain of NLRP3 is key for inflammasome activation.

Host: Dr. Miguel Segura Ginard, Senior researcher- Childhood Cancer and Blood Disorders (VHIR)

Register here to attend by Zoom: https://gencat.zoom.us/j/93529101286