Cryo-EM structures of the active NLRP3 inflammasome disc

Xiao, Le; Magupalli, Venkat Giri; Wu, Hao

doi:10.1038/s41586-022-05570-8

Cited by 133 publications

(100 citation statements)

References 61 publications

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“…I/R causes cell death, including apoptosis, autophagy, necrosis and pyroptosis. A number of studies have demonstrated that pyroptosis is triggered by NLRP3, AIM2-like receptor proteins and tripartite motif-containing protein and other inflammasomes ( 38 , 39 ). Following the stimulation of these inflammasomes, downstream inflammatory caspase-1 or caspase-11 is cleaved, leading to secretion of pro-inflammatory cytokines IL-1β and IL-18( 40 ).…”

Section: Discussionmentioning

confidence: 99%

miR‑30c reduces myocardial ischemia/reperfusion injury by targeting SOX9 and suppressing pyroptosis

Nie

Zhou

et al. 2023

Exp Ther Med

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MicroRNAs (miRNAs or miRs) are commonly involved in regulating myocardial ischemia/reperfusion (I/R) injury by binding and silencing their target genes. However, whether miRNAs regulate myocardial I/R-induced pyroptosis remains unclear. The present study established an in vivo rat model of myocardial I/R injury and in vitro hypoxia/reoxygenation (H/R) injury model in rat primary cardiomyocytes to investigate the function and the underlying mechanisms of miRNAs on I/R injury-induced pyroptosis. RNA sequencing was utilized to select the candidate miRNAs between normal and I/R group. Reverse transcription-quantitative PCR and western blotting were performed to detect candidate miRNAs (miR-30c-5p, also known as miR-30c) and SRY-related high mobility group-box gene 9 (SOX9) expression, as well as expression of pyroptosis-associated proteins (NF-κB, ASC, caspase-1, NLRP3) in the myocardial I/R model. ELISA was used to measure pyroptosis-associated inflammatory markers IL-18 and IL-1β. Moreover, the link between miR-30c and SOX9 was predicted using bioinformatics and luciferase reporter assay. In myocardial I/R injured rats, miR-30c was downregulated, while the expression of SOX9 was upregulated. Overexpression of miR-30c inhibited pyroptosis both in vivo and in vitro . Furthermore, miR-30c negatively regulated SOX9 expression by binding its 3'untranslated region. In conclusion, the miR-30c/SOX9 axis decreased myocardial I/R injury by suppressing pyroptosis, which may be a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

miR‑30c reduces myocardial ischemia/reperfusion injury by targeting SOX9 and suppressing pyroptosis

Nie

Zhou

et al. 2023

Exp Ther Med

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“…Recently, Le Xiao et al. have reported the cryo-EM structures of the active NLRP3 inflammasome disk; it is proposed that NEK7 breaks the inactive NLRP3 cage to transform NLRP3 into the active NLRP3 inflammasome disk ( 23 ).…”

Section: Mechanism Of Nlrp3 Inflammasome Activationmentioning

confidence: 99%

The mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors

Zhan

et al. 2023

Front. Immunol.

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NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is a cytosolic pattern recognition receptor (PRR) that recognizes multiple pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Once activated, NLRP3 initiates the inflammasome assembly together with the adaptor ASC and the effector caspase-1, leading to caspase-1 activation and subsequent cleavage of IL-1β and IL-18. Aberrant NLRP3 inflammasome activation is linked with the pathogenesis of multiple inflammatory diseases, such as cryopyrinassociated periodic syndromes, type 2 diabetes, non-alcoholic steatohepatitis, gout, and neurodegenerative diseases. Thus, NLRP3 is an important therapeutic target, and researchers are putting a lot of effort into developing its inhibitors. The review summarizes the latest advances in the mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors.

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“…The ultrastructure of the NLRP3 inflammasome has been recently described using cryogenic electron microscopy. It was shown that the NLRP3 inflammasome forms a disk-shaped structure, with the centrosomal kinase NEK7, and the adaptor protein ASC, which recruits the protease caspase-1 ( 108 ). For more details and an image of the NLRP3 assembly complex, we refer the readers to the recent article by Xiao et al.…”

Section: Nod-like Receptorsmentioning

confidence: 99%

The role of NOD-like receptors in innate immunity

et al. 2023

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The innate immune system in vertebrates and invertebrates relies on conserved receptors and ligands, and pathways that can rapidly initiate the host response against microbial infection and other sources of stress and danger. Research into the family of NOD-like receptors (NLRs) has blossomed over the past two decades, with much being learned about the ligands and conditions that stimulate the NLRs and the outcomes of NLR activation in cells and animals. The NLRs play key roles in diverse functions, ranging from transcription of MHC molecules to initiation of inflammation. Some NLRs are activated directly by their ligands, while other ligands may have indirect effects on the NLRs. New findings in coming years will undoubtedly shed more light on molecular details involved in NLR activation, as well as the physiological and immunological outcomes of NLR ligation.

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Cryo-EM structures of the active NLRP3 inflammasome disc

Cited by 133 publications

References 61 publications

miR‑30c reduces myocardial ischemia/reperfusion injury by targeting SOX9 and suppressing pyroptosis

miR‑30c reduces myocardial ischemia/reperfusion injury by targeting SOX9 and suppressing pyroptosis

The mechanism of NLRP3 inflammasome activation and its pharmacological inhibitors

The role of NOD-like receptors in innate immunity

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