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Non-decameric NLRP3 reveals a TGN/MTOC-distal pathway of inflammasome activation.

Nature communications

Authors: María Mateo-Tórtola, Inga V Hochheiser, Gaopeng Li, Lukas Funk, Atousa Hashemi, Xiao Liu, Jane Torp, Lena Erlebach, András Szolek, Jelena Grga, Francesca Bork, Jana S Müller, Deborah Kronenberg-Versteeg, Matthias Geyer, Alexander N R Weber, Ana Tapia-Abellán

The NLRP3 inflammasome contributes to a wide range of conditions from infections to Alzheimer's disease. NLRP3 forms an inactive decameric cage, that upon interaction with the trans-Golgi network (TGN) and microtubule organization center (MTOC), leads to inflammasome activation, yet whether non-decamer NLRP3 species form functional inflammasomes remains unclear. Here, we design a NLRP3 exon 3 deletion variant that forms low molecular weight NLRP3 assemblies. Spatially and dynamically highly resolved microscopy in THP-1 and human macrophages shows that nigericin, a K-dependent NLRP3 stimulus, can trigger two distinct activation pathways: (i) the rapidly engaged decameric cage-dependent pathway; and (ii) a decameric cage-independent, TGN/MTOC-distal, and slow-reacting pathway employed by low molecular weight NLRP3 species, that dominates in human neutrophils. Collectively, our results delineate two parallel yet biologically distinct NLRP3 activation pathways, thereby providing a framework to understand NLRP3-driven inflammation across a wide range of pathological context and cell types.

© 2026. The Author(s).

PMID: 42215451

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