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Mechanistic insights from inflammasome structures

Abstract

Inflammasomes are supramolecular complexes that form in the cytosol in response to pathogen-associated and damage-associated stimuli, as well as other danger signals that perturb cellular homoeostasis, resulting in host defence responses in the form of cytokine release and programmed cell death (pyroptosis). Inflammasome activity is closely associated with numerous human disorders, including rare genetic syndromes of autoinflammation, cardiovascular diseases, neurodegeneration and cancer. In recent years, a range of inflammasome components and their functions have been discovered, contributing to our knowledge of the overall machinery. Here, we review the latest advances in inflammasome biology from the perspective of structural and mechanistic studies. We focus on the most well-studied components of the canonical inflammasome — NAIP–NLRC4, NLRP3, NLRP1, CARD8 and caspase-1 — as well as caspase-4, caspase-5 and caspase-11 of the noncanonical inflammasome, and the inflammasome effectors GSDMD and NINJ1. These structural studies reveal important insights into how inflammasomes are assembled and regulated, and how they elicit the release of IL-1 family cytokines and induce membrane rupture in pyroptosis.

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Fig. 1: The canonical and noncanonical inflammasome pathways.
Fig. 2: The NAIP–NLRC4 inflammasome.
Fig. 3: The NLRP3 inflammasome.
Fig. 4: The NLRP1 inflammasome.
Fig. 5: Gasdermins.
Fig. 6: NINJ1.

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Acknowledgements

We apologize for incomplete citations owing to space limitations. The work was supported by the National Institutes of Health grants AI124491, AI139914 and AI177778 to H.W. and by the National Health and Medical Research Council of Australia grants 2009677 and 2009075 to K.S.

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J.F. drafted the article, and all authors edited the article before submission.

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Correspondence to Hao Wu.

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H.W. is a co-founder and chair of the Scientific Advisory Board of Ventus Therapeutics. K.S. is a co-inventor on patent applications for NLRP3 inhibitors that have been licensed to Inflazome Ltd, which was acquired by Roche. K.S. served on the Scientific Advisory Board of Inflazome, Ireland, and Quench Bio, USA, and serves on a Scientific Advisory Board for Novartis, Switzerland. J.F. declares no competing interests.

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Glossary

Alarmin

Alarmins are proteins, peptides, metabolites or others that are released to the outside of a cell in response to immune activation, as a result of transmembrane pore formation, cell injury and lytic death, or degranulation. These endogenous molecules may have chemotactic and/or immune-activating properties to alert the host for defence.

Cryopyrin-associated periodic syndromes

(CAPS). A set of genetic diseases of differing severity caused by autosomal dominant mutations in NLRP3. Patients with CAPS develop spontaneous inflammation and excessive release of the cytokine IL-1β, and may also suffer from arthralgia, deafness and hives.

Microtubule-organizing centre

(MTOC). A structure in eukaryotic cells from which microtubules are nucleated and emanate, which is often synonymous with the centrosome.

Neutrophil extracellular traps

Web-like networks of extracellular DNA, histones and neutrophil granule proteins extruded by neutrophils to trap and damage pathogens.

Pyroptosis

Programmed lytic cell death mediated by cleavage of gasdermin D by caspase-1, caspase-4, caspase-5 and caspase-11, or by other gasdermin family members, that occurs downstream of inflammasome activation or other insults.

Ribotoxic stress response

Activation of stress-associated kinases such as p38 and JNK1 owing to functional ribosome defects that result in inhibition or partial inhibition of protein translation. Downstream signalling can trigger cell cycle arrest, cell death and cytokine production.

Type III secretion

A bacterial secretion system involving a needle-like protein complex used to deliver effector proteins into the host cell cytosol; often found in pathogenic Gram-negative bacteria.

Unfolded protein response

A stress response resulting from the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum that helps cells to reduce the stress through translation suppression, protein degradation and production of chaperones, or that induces cell death with prolonged stress.

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Fu, J., Schroder, K. & Wu, H. Mechanistic insights from inflammasome structures. Nat Rev Immunol 24, 518–535 (2024). https://doi.org/10.1038/s41577-024-00995-w

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