Cofilin-1 is a redox-sensitive guard of the NLRP3 inflammasome

Cofilin-1 is a redox-sensitive guard of the NLRP3 inflammasome

  • Fu, J., Schroder, K. & Wu, H. Mechanistic insights from inflammasome structures. Nat. Rev. Immunol. 24, 518–535 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hoffman, H. M., Mueller, J. L., Broide, D. H., Wanderer, A. A. & Kolodner, R. D. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat. Genet. 29, 301–305 (2001).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Aksentijevich, I. et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 46, 3340–3348 (2002).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol. 9, 857–865 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Heneka, M. T. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mauro, A. G. et al. The role of NLRP3 inflammasome in pericarditis: potential for therapeutic approahces. JACC Basic Transl. Sci. 6, 137–150 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vecchie, A. et al. Interleukin-1 and the NLRP3 inflammasome in pericardial disease. Curr. Cardiol. Rep. 23, 157 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Andreeva, L. et al. NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation. Cell 184, 6299–6312 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • He, Y., Zeng, M. Y., Yang, D., Motro, B. & Nunez, G. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature 530, 354–357 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shi, H. et al. NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat. Immunol. 17, 250–258 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schmacke, N. A. et al. IKKβ primes inflammasome formation by recruiting NLRP3 to the trans-Golgi network. Immunity 55, 2271–2284 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Petrilli, V. et al. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 14, 1583–1589 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bruchard, M. et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the NLRP3 inflammasome and promotes tumor growth. Nat. Med. 19, 57–64 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tassi, S. et al. Altered redox state of monocytes from cryopyrin-associated periodic syndromes causes accelerated IL-1β secretion. Proc. Natl Acad. Sci. USA 107, 9789–9794 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Balow, J. E. Jr. et al. Microarray-based gene expression profiling in patients with cryopyrin-associated periodic syndromes defines a disease-related signature and IL-1-responsive transcripts. Ann. Rheum. Dis. 72, 1064–1070 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Park, Y. H., Wood, G., Kastner, D. L. & Chae, J. J. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat. Immunol. 17, 914–921 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Burger, D., Fickentscher, C., de Moerloose, P. & Brandt, K. J. F-actin dampens NLRP3 inflammasome activity via Flightless-I and LRRFIP2. Sci. Rep. 6, 29834 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, G. S. et al. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492, 123–127 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gross, C. J. et al. K+ efflux-independent NLRP3 inflammasome activation by small molecules targeting mitochondria. Immunity 45, 761–773 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Abramson, J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature 630, 493–500 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Finkel, T. Signal transduction by reactive oxygen species. J. Cell Biol. 194, 7–15 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Klemke, M. et al. Oxidation of cofilin mediates T cell hyporesponsiveness under oxidative stress conditions. Immunity 29, 404–413 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Klejnot, M. et al. Analysis of the human cofilin 1 structure reveals conformational changes required for actin binding. Acta Crystallogr. D Biol. Crystallogr. 69, 1780–1788 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cameron, J. M. et al. Polarized cell motility induces hydrogen peroxide to inhibit cofilin via cysteine oxidation. Curr. Biol. 25, 1520–1525 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Coll, R. C. et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21, 248–255 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hochheiser, I. V. et al. Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3. Nature 604, 184–189 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Munoz-Planillo, R. et al. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38, 1142–1153 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pfannstiel, J. et al. Human cofilin forms oligomers exhibiting actin bundling activity. J. Biol. Chem. 276, 49476–49484 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Leaver-Fay, A. et al. ROSETTA3: an object-oriented software suite for the simulation and design of macromolecules. Methods Enzymol. 487, 545–574 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Goddard, T. D. et al. UCSF ChimeraX: meeting modern challenges in visualization and analysis. Protein Sci. 27, 14–25 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Honorato, R. V. et al. The HADDOCK2.4 web server for integrative modeling of biomolecular complexes. Nat. Protoc. 19, 3219–3241 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xiao, L., Magupalli, V. G. & Wu, H. Cryo-EM structures of the active NLRP3 inflammasome disc. Nature 613, 595–600 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sharif, H. et al. Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature 570, 338–343 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cheng, J. et al. Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 381, eadg7492 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schubach, M., Maass, T., Nazaretyan, L., Roner, S. & Kircher, M. CADD v1.7: using protein language models, regulatory CNNs and other nucleotide-level scores to improve genome-wide variant predictions. Nucleic Acids Res. 52, D1143–D1154 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ioannidis, N. M. et al. REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am. J. Hum. Genet. 99, 877–885 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Duncan, J. A. et al. Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc. Natl Acad. Sci. USA 104, 8041–8046 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brinkschulte, R. et al. ATP-binding and hydrolysis of human NLRP3. Commun. Biol. 5, 1176 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Liston, A. & Masters, S. L. Homeostasis-altering molecular processes as mechanisms of inflammasome activation. Nat. Rev. Immunol. 17, 208–214 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Feng, S. et al. Mechanisms of NLRP3 activation and inhibition elucidated by functional analysis of disease-associated variants. Nat. Immunol. 26, 511–523 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cosson, C. et al. Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation. J. Exp. Med. 221, e20231200 (2024).

  • Yu, X. et al. Structural basis for the oligomerization-facilitated NLRP3 activation. Nat. Commun. 15, 1164 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jones, J. D. & Dangl, J. L. The plant immune system. Nature 444, 323–329 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Koenen, T. B. et al. Hyperglycemia activates caspase-1 and TXNIP-mediated IL-1β transcription in human adipose tissue. Diabetes 60, 517–524 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Masters, S. L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897–904 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Klamt, F. et al. Oxidant-induced apoptosis is mediated by oxidation of the actin-regulatory protein cofilin. Nat. Cell Biol. 11, 1241–1246 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hoffmann, L. et al. Cofilin1 oxidation links oxidative distress to mitochondrial demise and neuronal cell death. Cell Death Dis. 12, 953 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Paunovska, K., Loughrey, D. & Dahlman, J. E. Drug delivery systems for RNA therapeutics. Nat. Rev. Genet. 23, 265–280 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Taya, T., Kami, D., Teruyama, F., Matoba, S. & Gojo, S. Peptide-encoding gene transfer to modulate intracellular protein–protein interactions. Mol. Ther. Methods Clin. Dev. 32, 101226 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, H. et al. Therapeutic potential of MCC950, a specific inhibitor of NLRP3 inflammasome. Eur. J. Pharmacol. 928, 175091 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tang, F. et al. First-in-human phase 1 trial evaluating safety, pharmacokinetics, and pharmacodynamics of NLRP3 inflammasome inhibitor, GDC-2394, in healthy volunteers. Clin. Transl. Sci. 16, 1653–1666 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chae, J. J. et al. Gain-of function pyrin mutations induces NLRP3 protein-independent interleukin-1 activation and severe autoinflammation in mice. Immunity 34, 755–768 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • The PyMOL Molecular Graphics System, Version 3.0 (Schrödinger, 2023).

  • Pires, D. E., Ascher, D. B. & Blundell, T. L. mCSM: predicting the effects of mutations in proteins using graph-based signatures. Bioinformatics 30, 335–342 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pires, D. E., Ascher, D. B. & Blundell, T. L. DUET: a server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Res. 42, W314–W319 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rodrigues, C. H., Pires, D. E. & Ascher, D. B. DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability. Nucleic Acids Res. 46, W350–W355 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rodrigues, C. H. M., Pires, D. E. V. & Ascher, D. B. DynaMut2: assessing changes in stability and flexibility upon single and multiple point missense mutations. Protein Sci. 30, 60–69 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhou, Y., Pan, Q., Pires, D. E. V., Rodrigues, C. H. M. & Ascher, D. B. DDMut: predicting effects of mutations on protein stability using deep learning. Nucleic Acids Res. 51, W122–W128 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Worth, C. L., Preissner, R. & Blundell, T. L. SDM—a server for predicting effects of mutations on protein stability and malfunction. Nucleic Acids Res. 39, W215–W222 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Frappier, V., Chartier, M. & Najmanovich, R. J. ENCoM server: exploring protein conformational space and the effect of mutations on protein function and stability. Nucleic Acids Res. 43, W395–W400 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhou, Y., Myung, Y., Rodrigues, C. H. M. & Ascher, D. B. DDMut-PPI: predicting effects of mutations on protein-protein interactions using graph-based deep learning. Nucleic Acids Res. 52, W207–W214 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rodrigues, C. H. M., Myung, Y., Pires, D. E. V. & Ascher, D. B. mCSM-PPI2: predicting the effects of mutations on protein–protein interactions. Nucleic Acids Res. 47, W338–W344 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, S. et al. A genomic mutational constraint map using variation in 76,156 human genomes. Nature 625, 92–100 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xue, L. C., Rodrigues, J. P., Kastritis, P. L., Bonvin, A. M. & Vangone, A. PRODIGY: a web server for predicting the binding affinity of protein–protein complexes. Bioinformatics 32, 3676–3678 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kim, D. E., Chivian, D. & Baker, D. Protein structure prediction and analysis using the Robetta server. Nucleic Acids Res. 32, W526–W531 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar