Journal Article

DZNE-2026-00585

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Non-decameric NLRP3 reveals a TGN/MTOC-distal pathway of inflammasome activation.

Mateo-Tórtola, M. ; Hochheiser, I. V. ; Li, G. ; Funk, L. ; Hashemi, A. ; Liu, X. ; Torp, J. ; Erlebach, L.DZNE* ; Szolek, A. ; Grga, J. ; Bork, F. ; Müller, J. S. ; Kronenberg-Versteeg, D.DZNE* ; Geyer, M. ; Weber, A. N. R. ; Tapia-Abellán, A.

2026
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41467-026-72627-x

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.

Keyword(s): Humans (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: metabolism (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: genetics (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: chemistry (MeSH) ; Inflammasomes: metabolism (MeSH) ; Inflammasomes: genetics (MeSH) ; Macrophages: metabolism (MeSH) ; Macrophages: drug effects (MeSH) ; Macrophages: immunology (MeSH) ; trans-Golgi Network: metabolism (MeSH) ; THP-1 Cells (MeSH) ; Nigericin: pharmacology (MeSH) ; Neutrophils: metabolism (MeSH) ; Signal Transduction (MeSH) ; Microtubules: metabolism (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein ; Inflammasomes ; NLRP3 protein, human ; Nigericin

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Contributing Institute(s):

1. Cell Biology of Neurological Diseases (AG Jucker)
2. Glial Cell Biology (AG Kronenberg-Versteeg)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 351 - Brain Function (POF4-351) (POF4-351)

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