ArticleNature immunology2025
Mechanisms of NLRP3 activation and inhibition elucidated by functional analysis of disease-associated variants.
Article in Nature immunology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers, 1 of them a synthesis that pooled it.
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Who cites it
58 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Prognostic significance of NLRP-3 expression in solid cancers: a systematic review and meta-analysis.Annals of medicine · 2026Pooled it
- Targeting integrated cell death networks in sepsis‑associated acute kidney injury: Shared regulatory nodes and diet‑related small molecule modulation (Review).International journal of molecular medicine · 2026Review
- Integrative multi-omics reveals CUL4B as a modulator of macrophage pyroptosis and innate defense againstScience advances · 2026Article
- Structural mechanisms of SAMD9 autoinhibition and pathogenic dysregulation.Science advances · 2026Article
- ACSL4-Dependent Lysosomal Lipid Peroxidation Links WTAP-Mediated mAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Plant-Derived Exosome-like Nanovesicles for Metabolic Dysfunction-Associated Steatotic Liver Disease.Veterinary sciences · 2026Review
- Thymosin β4 Mitigates Acute Cerebral Infarction Via Inhibition of the TLR4/NF-κB Pathway and Suppression of Neuronal Pyroptosis.Applied biochemistry and biotechnology · 2026Article
- Protein-protein interaction-mediated signaling networks in ischemic stroke: from molecular mechanisms to therapeutic strategies.Acta pharmacologica Sinica · 2026Review
- Ginkgo biloba L. in preventing cardiovascular disease: pharmacological effects, mechanism of action, and therapeutic potential.Acta pharmacologica Sinica · 2026Review
- Mapping human microglial morphological diversity via handcrafted and deep learning-derived image features.iScience · 2026Article
- PAD4-generated citrullinated histones are triggers for autoinflammation in cryopyrin-associated periodic syndrome.Cell death and differentiation · 2026Article
- Decoding variants of uncertain significance in systemic autoinflammatory diseases.Nature reviews. Rheumatology · 2026Review
- Mitigation of renal tubular injury by SIRT6 may improve individual outcomes in diabetic kidney disease-potential mechanisms involving epigenetic repression of inflammatory responses.Journal of advanced research · 2026Article
- Pharmacological targeting of the NLRP3 LRR domain with isothiazolinones overcomes CRID3-resistant inflammation.EMBO molecular medicine · 2026Article
- Stage-dependent role of NEK7 in the inactive-to-active conformational transition of NLRP3 monomer.PLoS computational biology · 2026Article
- Review
- Sensing the spectrum: diverse stimuli for the NLRP3 inflammasome.Communications biology · 2026Review
- AI platform for CRISPR functional mapping and function-based drug design.bioRxiv : the preprint server for biology · 2026Article
- SYK Signalling in NLRP3 Inflammasome-Mediated Response of Murine Microglia Activated by Immune Complexes Formed of Viral Proteins and Specific IgG.European journal of immunology · 2026Article
- Pyroptosis in cerebral ischemia‑reperfusion injury: Molecular mechanisms and therapeutic implications (Review).Molecular medicine reports · 2026Review
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Authors and funding
18 authors.
Funding
Abstract
The NLRP3 inflammasome is a multiprotein complex that mediates caspase-1 activation and the release of proinflammatory cytokines, including interleukin (IL)-1β and IL-18. Gain-of-function variants in the gene encoding NLRP3 (also called cryopyrin) lead to constitutive inflammasome activation and excessive IL-1β production in cryopyrin-associated periodic syndromes (CAPS). Here we present functional screening and automated analysis of 534 NLRP3 variants from the international INFEVERS registry and the ClinVar database. This resource captures the effect of NLRP3 variants on ASC speck formation spontaneously, at low temperature, after inflammasome stimulation and with the specific NLRP3 inhibitor MCC950. Most notably, our analysis facilitated the updated classification of NLRP3 variants in INFEVERS. Structural analysis suggested multiple mechanisms by which CAPS variants activate NLRP3, including enhanced ATP binding, stabilizing the active NLRP3 conformation, destabilizing the inactive NLRP3 complex and promoting oligomerization of the pyrin domain. Furthermore, we identified pathogenic variants that can hypersensitize the activation of NLRP3 in response to nigericin and cold temperature exposure. We also found that most CAPS-related NLRP3 variants can be inhibited by MCC950; however, NLRP3 variants with changes to proline affecting helices near the inhibitor binding site are resistant to MCC950, as are variants in the pyrin domain, which likely trigger activation directly with the pyrin domain of ASC. Our findings could help stratify the CAPS population for NLRP3 inhibitor clinical trials and our automated methodologies can be implemented for molecules with a different mechanism of activation and in laboratories worldwide that are interested in adding new functionally validated NLRP3 variants to the resource. Overall, our study provides improved diagnosis for patients with CAPS, mechanistic insight into the activation of NLRP3 and stratification of patients for the future application of targeted therapeutics.
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