Non-decameric NLRP3 reveals a TGN/MTOC-distal pathway of inflammasome activation
Abstract 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.
Authors
- Francesca Bork (ORCID: https://orcid.org/0000-0002-5073-4243)
- Atousa Hashemi
- Jane Torp (ORCID: https://orcid.org/0000-0003-3257-8483)
- Maria Mateo Tortola (ORCID: https://orcid.org/0000-0002-3412-2028)
- Lena Erlebach (ORCID: https://orcid.org/0000-0002-9077-8689)
- András Szolek (ORCID: https://orcid.org/0000-0003-4758-7817)
- Inga V. Hochheiser (ORCID: https://orcid.org/0000-0001-6649-2624)
- Jelena Grga
- Lukas Funk
- Gaopeng Li
- Jana S. Müller
- Deborah Kronenberg-Versteeg (ORCID: https://orcid.org/0000-0003-0965-9998)
- Matthias Geyer (ORCID: https://orcid.org/0000-0002-7718-5002)
- Alexander N. R. Weber (ORCID: https://orcid.org/0000-0002-8627-7056)
- Xiao Liu
- Ana Tapia-Abellán (ORCID: https://orcid.org/0000-0002-6235-4248)
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Bonn (DE)
- Institut National des Sciences Appliquées de Toulouse (FR)
- University Hospital Bonn (DE)
- BG Klinik Tübingen (DE)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Toulouse Mathematics Institute (FR)
- Innovation Cluster (Canada) (CA)
- Hertie Institute for Clinical Brain Research (DE)
- Santa Lucía University General Hospital (ES)
- Universidad de Murcia (ES)
- University of Tübingen (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-30
- DOI
- https://doi.org/10.1038/s41467-026-72627-x
- Primary Topic
- Inflammasome and immune disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Ministerio de Ciencia, Innovación y Universidades
- Deutsche Forschungsgemeinschaft
- Volkswagen Foundation
- Eberhard Karls Universität Tübingen
- Universidad de Murcia
- Universitetet i Oslo
- Uppsala Universitet
- Association Neurofibromatoses et Recklinghause
- Agencia Estatal de Investigación
- European Social Fund