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bioRxiv · 10.1101/2023.07.07.548075

Non-decameric NLRP3 forms an MTOC-independent inflammasome

Mateo-Tortola, M.·Hochheiser, I. V.·Grga, J.·Mueller, J. S.·Geyer, M.·Weber, A. N. R.·Tapia-Abellan, A.
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Abstract

NLRP3 is an inflammasome-forming protein that plays a key role in conditions ranging from infections to Alzheimers disease. NLRP3 is activated by many potassium (K+)-dependent or - independent stimuli related to pathogens or sterile insults. Molecularly, human NLRP3 assembles into a decameric cage and its interaction with both the trans-Golgi network (TGN) and the microtubule organization centre (MTOC) has been proposed as critical for NLRP3 activation. However, the relative mechanistic requirement for K+-dependent versus - independent stimuli is unclear. Using spatially and dynamically high-resolution microscopy in human macrophages, we found that K+-dependent NLRP3 stimulation triggers two distinct activation pathways: (i) the decameric cage-dependent pathway, which was also exclusively required for the K+-independent stimulus, imiquimod; and (ii) a cage- and TGN/MTOC-independent pathway that was fully functional in an NLRP3 protein engineered to form monomers and unable to interact with membrane lipids. Collectively, our results delineate two parallel yet biologically distinct NLRP3 activation pathways.

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Mateo-Tortola, M., Hochheiser, I. V., Grga, J., Mueller, J. S., Geyer, M., Weber, A. N. R., Tapia-Abellan, A.. 2023-07-07. Non-decameric NLRP3 forms an MTOC-independent inflammasome. https://doi.org/10.1101/2023.07.07.548075

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