Non-decameric NLRP3 reveals a TGN/MTOC-distal pathway of inflammasome activation
- 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
2026-05-30
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.