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The scaffolding and activation of NLRP3 on acidic vesicles depends on their biophysical properties and is independent of intermediate filaments

Guillermo A de Paz Linares,J. Mossemann,B. Sayed,S. Freeman

Published 2025 in bioRxiv

ABSTRACT

Inflammasomes are nucleated by receptors that become activated upon cellular stresses including ionic dyshomeostasis. Rather than forming in the cytosol, recent evidence suggests that inflammasomes are nucleated at specific sites in the cell including on cytoskeletal polymers and the membrane surfaces of organelles. The NLRP3 inflammasome, which is formed upon the loss of cytosolic K+, had been proposed to form on intermediate filaments as well as on vesicles along the endocytic pathway. To determine the necessary requirement of either mechanism, we used vimentin knockout macrophages which do not have intermediate filaments and compared the formation and function of NLRP3 inflammasomes. We report that vimentin was dispensable for the activation of caspase-1, IL-1β cleavage and release, and inflammatory responses in mice attributed to the inflammasome. Instead, NLRP3 was recruited to PI(3,5)P2, PI(4)P- and LAMP1-positive compartments undergoing osmotic swelling. Swelling of these compartments was dependent on the V-ATPase, the inhibition of which curtailed NLRP3 recruitment and inflammasome activation. Similarly, decreasing the hydrostatic pressure on these vesicles prevented NLRP3 recruitment, IL-1β release and pyroptosis. The results suggest that NLRP3 is activated by biophysical features of acidic organelles in the endocytic pathway.

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