NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation
Open accessPublished version of a preprint
Abstract
The NACHT-, leucine-rich-repeat- (LRR), and pyrin domain-containing protein 3 (NLRP3) is emerging to be a critical intracellular inflammasome sensor of membrane integrity and a highly important clinical target against chronic inflammation. Here, we report that an endogenous, stimulus-responsive form of full-length mouse NLRP3 is a 12- to 16-mer double-ring cage held together by LRR-LRR interactions with the pyrin domains shielded within the assembly to avoid premature activation. Surprisingly, this NLRP3 form is predominantly membrane localized, which is consistent with previously noted localization of NLRP3 at various membrane organelles. Structure-guided mutagenesis reveals that trans-Golgi network dispersion into vesicles, an early event observed for many NLRP3-activating stimuli, requires the double-ring cages of NLRP3. Double-ring-defective NLRP3 mutants abolish inflammasome punctum formation, caspase-1 processing, and cell death. Thus, our data uncover a physiological NLRP3 oligomer on the membrane that is poised to sense diverse signals to induce inflammasome activation.
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Cites
Fiji: an open-source platform for biological-image analysis
Schindelin, J., Arganda-Carreras, I., Frise, E., Kaynig, V., Longair, M., Pietzsch, T., Preibisch, S., Rueden, C., Saalfeld, S., Schmid, B., et al. (2012) · Nature Methods · doi:10.1038/nmeth.2019 · Cited by 66,890 · see citing works
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
A role for mitochondria in nlrp3 inflammasome activation
Zhou, R., Yazdi, A. S., Menu, P., & Tschopp, J. (2011) · Nature · doi:10.1038/nature09663 · Cited by 5,602 · see citing works
Gout-associated uric acid crystals activate the NALP3 inflammasome
Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A., & Tschopp, J. (2006) · Nature · doi:10.1038/nature04516 · Cited by 5,326 · see citing works
Cryopyrin activates the inflammasome in response to toxins and ATP
Mariathasan, S., Weiss, D. S., Newton, K., McBride, J., O'Rourke, K., Roose-Girma, M., Lee, W. P., Weinrauch, Y., Monack, D. M., & Dixit, V. M. (2006) · Nature · doi:10.1038/nature04515 · Cited by 3,080 · see citing works
A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases
Coll, R. C., Robertson, A. A. B., Chae, J. J., Higgins, S. C., Muñoz-Planillo, R., Inserra, M. C., Vetter, I., Dungan, L. S., Monks, B. G., Stutz, A., et al. (2015) · Nature Medicine · doi:10.1038/nm.3806 · Cited by 2,849 · see citing works
K+ regulates Ca2+ to drive inflammasome signaling: dynamic visualization of ion flux in live cells
Yaron, J. R., Gangaraju, S., Rao, M. Y., Kong, X., Zhang, L., Su, F., Tian, Y., Glenn, H. L., & Meldrum, D. R. (2015) · Cell Death & Disease · doi:10.1038/cddis.2015.277 · Cited by 212 · cited 1× · see citing works
“Because almost all NLRP3-activating stimuli converge to K efflux (Muñoz-Planillo et al., 2013; Yaron et al., 2015), it is reasonable”
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Xian, H., Watari, K., Sanchez-Lopez, E., Offenberger, J., Onyuru, J., Sampath, H., Ying, W., Hoffman, H. M., Shadel, G. S., & Karin, M. (2022) · Immunity · doi:10.1016/j.immuni.2022.06.007 · Cited by 850 · see citing works
Blevins, H. M., Xu, Y., Biby, S., & Zhang, S. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.879021 · Cited by 587 · see citing works
Structural basis for the oligomerization-facilitated NLRP3 activation
Yu, X., Matico, R. E., Miller, R., Chauhan, D., Van Schoubroeck, B., Grauwen, K., Suarez, J., Pietrak, B., Haloi, N., Yin, Y., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45396-8 · Cited by 78 · see citing works
- Authors
- Andreeva, L., David, L., Rawson, S., Shen, C., Pasricha, T., Pelegrin, P., & Wu, H.
- Affiliations
- Boston Children's Hospital (US)
- Harvard University (US)
- Corresponding author
- Wu, Hao
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 184
- Issue
- 26
- Pages
- 6299-6312.e22
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8763037
- OpenAlex
- W3216744349
- Cited by
- 292
- References
- 7
- Citations by year
- 2026: 60 · 2025: 64 · 2024: 66 · 2023: 50 · 2022: 49 · 2021: 3
- FWCI
- 13.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 386 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AI124491, HD087988)
- Cancer Research Institute
- Damon Runyon Cancer Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- NLRP3 inflammasome, inflammasome activation, pyrin domain, membrane localization, trans-Golgi network, cell death, structure-guided mutagenesis, chronic inflammation
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, NIMA-Related Kinases, Protein Domains, Amino Acid Sequence, Animals, Cell Membrane, Humans, Models, Biological, Models, Molecular, Mutation, Nigericin, Protein Binding, Cryoelectron Microscopy, trans-Golgi Network, Mice, Protein Multimerization, HEK293 Cells, Inflammasomes
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