4.6 Review

The human inflammasomes

Related references

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Editorial Material Cell Biology

How to dodge pyroptosis: lessons from Shigella flexneri

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Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3

Inga Hochheiser et al.

Summary: This study determined the conformational states of human NLRP3 and its interaction with the inhibitor CRID3 through cryo-electron microscopy. The findings provide insights into the regulatory mechanism of NLRP3 and offer potential for the treatment of related diseases.

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Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells

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Summary: The activation of inflammasomes plays a crucial role in regulating the infection of SARS-CoV-2. Lung epithelial cells serve as the primary entry site of the virus and express the inflammasome-forming sensor NLRP1. The cleavage of NLRP1 by coronavirus 3CL proteases leads to inflammasome assembly, cell death, and reduced production of viral particles. Additionally, these proteases also inactivate the executioner protein Gasdermin D, promoting an alternative form of cell death called pyroptosis. Analysis of pyroptosis markers in COVID-19 patients suggests that GSDME/caspase-3 could potentially serve as markers of disease severity.

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NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation

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Summary: The NLRP3 protein forms a double-ring structure held together by LRR-LRR interactions, predominantly localized on the cell membrane, ready to sense various signals to induce inflammasome activation.
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Human NLRP1 is a sensor for double-stranded RNA

Stefan Bauernfried et al.

Summary: Inflammasomes play a crucial role as intracellular sensors in pathogen infection and cellular perturbation. Human NLRP1 has been identified as a direct sensor for dsRNA, triggering activation during RNA virus infection. The NLRP1 complex binds dsRNA through its leucine-rich repeat domain, leading to activation through adenosine triphosphatase activity in its NACHT domain.

SCIENCE (2021)

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Diverse viral proteases activate the NLRP1 inflammasome

Brian Tsu et al.

Summary: The NLRP1 inflammasome can be activated by proteases from various picornaviruses within a rapidly evolving region of the protein, leading to host-specific and virus-specific activation. This suggests that host mimicry of viral polyprotein cleavage sites can be an evolutionary strategy to trigger a strong inflammatory response.

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Escherichia coli Rho GTPase-activating toxin CNF1 mediates NLRP3 inflammasome activation via p21-activated kinases-1/2 during bacteraemia in mice

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Summary: Inflammasomes are critical signalling platforms assembled in response to infection or sterile inflammation, with NLRP3 playing a key role in activating the inflammasome. The activation of NLRP3 inflammasome is tightly controlled both transcriptionally and post-translationally, but the mechanisms regulating its activation remain poorly understood.

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Crystal Structure of NLRP3 NACHT Domain With an Inhibitor Defines Mechanism of Inflammasome Inhibition

Carien Dekker et al.

Summary: The NLRP3 inflammasome responds to various pathogenic and sterile signals, producing interleukin-1 beta and interleukin-18. Understanding the structure of NLRP3 NACHT domain can provide insights into activation mechanisms and aid in the development of inhibitors for inflammatory diseases. Stabilizing the auto-inhibited form of the NACHT domain is an effective strategy to inhibit NLRP3 and could be beneficial in future therapeutic approaches.

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Shigella evades pyroptosis by arginine ADP-riboxanation of caspase-11

Zilin Li et al.

Summary: This study identified a novel post-translational modification, ADP riboxanation, mediated by the Shigella effector OspC3, which inactivates the LPS sensing pathway of caspase-4 and caspase-11 and prevents pyroptosis. ADP riboxanation modification on Arg314 and Arg310 in caspase-4 and caspase-11 inhibits their activity, leading to evasion of host defense against Shigella infection. This bacterial virulence mechanism highlights the importance of ADP riboxanation in preventing LPS-induced pyroptosis.

NATURE (2021)

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CARD8 is an inflammasome sensor for HIV-1 protease activity

Qiankun Wang et al.

Summary: HIV-1's rapid evolution and high mutation rates enable it to evade the host immune system, but intervention targeting the protease activity with the inflammasome sensor CARD8 has shown promise in clearing latent HIV-1 infection.

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Article Multidisciplinary Sciences

DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation

L. Robert Hollingsworth et al.

Summary: NLRP1 is an inflammasome sensor that mediates caspase-1 activation, and its function is regulated by DPP8/DPP9, with VbP disrupting the NLRP1-DPP9 interaction to accelerate inflammasome activation.

NATURE (2021)

Article Multidisciplinary Sciences

Structural and biochemical mechanisms of NLRP1 inhibition by DPP9

Menghang Huang et al.

Summary: The study demonstrates that full-length rat NLRP1 and rat DPP9 can form a complex to suppress NLRP1 activation. The ZU5 domain is essential for both autoinhibition of NLRP1 and assembly of the complex. Furthermore, both NLRP1 binding and enzymatic activity are required for DPP9 to suppress NLRP1 in human cells.

NATURE (2021)

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Shigella ubiquitin ligase IpaH7.8 targets gasdermin D for degradation to prevent pyroptosis and enable infection

Giovanni Luchetti et al.

Summary: The study reveals the mechanism by which IpaH7.8 from Shigella ubiquitinates human GSDMD and targets it for proteasomal degradation, contributing to the bacterium's impact on humans rather than mice.

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AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host defence

SangJoon Lee et al.

Summary: Inflammasomes are essential for innate immune defence, sensing pathogens and inducing cell death. They can detect multiple molecular patterns released by live pathogens during infection, activating multiple inflammasome sensors simultaneously. The study found that AIM2 regulates innate immune sensors pyrin and ZBP1 to drive inflammatory signalling and a form of inflammatory cell death known as PANoptosis, providing host protection during infections with specific pathogens.

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CARD8 inflammasome activation triggers pyroptosis in human T cells

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Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia

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DPP8/9 inhibitors activate the CARD8 inflammasome in resting lymphocytes

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Priming Is Dispensable for NLRP3 Inflammasome Activation in Human MonocytesIn Vitro

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Caspase-1 interdomain linker cleavage is required for pyroptosis

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N-terminal degradation activates the NLRP1B inflammasome

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Human Monocytes Engage an Alternative Inflammasome Pathway

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Site-specific phosphorylation and microtubule dynamics control Pyrin inflammasome activation

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Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation

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IRAK-1 bypasses priming and directly links TLRs to rapid NLRP3 inflammasome activation

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Human NAIP and mouse NAIP1 recognize bacterial type III secretion needle protein for inflammasome activation

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CARD8 and NLRP1 Undergo Autoproteolytic Processing through a ZU5-Like Domain

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Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3

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Gout-associated uric acid crystals activate the NALP3 inflammasome

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