Structural Basis for NLRP6 Inflammasome Assembly and Activation

Abstract

Inflammasomes are multi‐protein complexes that detect infectious microbes and cellular stressors, and that activate inflammatory caspases for cytokine maturation and pyroptosis. NLRP6, a sensor protein in the nucleotide‐binding domain (NBD) and leucine‐rich repeat (LRR)containing (NLR) family, is shown to play multiple roles in regulation of inflammation and other innate immune signaling pathways. However, little is known about the molecular mechanism of NLRP6 inflammasome assembly and activation. Using cryo‐Electron Microscopy (Cryo‐EM) and X‐ray crystallography, we found that NLRP6 PYD domain is able to self‐assemble into filamentous structures accompanied by large conformational changes, and can recruit the adaptor protein ASC through homotypic PYD/PYD interactions. We further observed that full‐length NLRP6 assembles into wider filaments in a concentration dependent manner with a PYD core surrounded by the NBD and LRR domain. In conclusion, our results indicate a unified filamentous assembly mode of NLRP family proteins for downstream signal transduction. These findings will be of value for researchers to conceive the structural study of full‐length NLRP inflammasomes.Support or Funding InformationThis work was supported by US National Institutes of Health grants Al124491 and HD087988 (to H.W.) and the Harvard Digestive and Disease Center Grant HDDC P30 DK034854 (to T.M.F.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.