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bioRxiv · 10.1101/2024.09.12.612739

Human NLRP3 inflammasome activation leads to formation of condensate at the microtubule organizing center

Wang, J.·Wu, M.·Magupalli, V.·Dahlberg, P.·Wu, H.·Jensen, G.
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Abstract

The NLRP3 inflammasome is a multi-protein molecular machine that mediates inflammatory responses in innate immunity. Its dysregulation has been linked to a large number of human diseases. Using cryogenic fluorescence-guided focused-ion-beam (cryo-FIB) milling and electron cryo-tomography (cryo-ET), we obtained 3-D images of the NLRP3 inflammasome in situ at various stages of its activation at macromolecular resolution. The cryo-tomograms unexpectedly reveal dense condensates of the human macrophage NLRP3 inflammasome that form within and around the microtubule organizing center (MTOC). We also find that following activation, the trans-Golgi network disperses and 50-nm NLRP3-associated vesicles appear which likely ferry NLRP3 to the MTOC. At later time points after activation, the electron-dense condensates progressively solidify and the cells undergo pyroptosis with widespread damaged mitochondria and autophagasomal structures.

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Wang, J., Wu, M., Magupalli, V., Dahlberg, P., Wu, H., Jensen, G.. 2024-09-15. Human NLRP3 inflammasome activation leads to formation of condensate at the microtubule organizing center. https://doi.org/10.1101/2024.09.12.612739

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