Initial description of the human NLRP3 promoter

Anderson, Justin P.; Mueller, James L.; Misaghi, Amir; Anderson, Scott; Sivagnanam, Mamata; Kolodner, Richard D.; Hoffman, Hal M.

doi:10.1038/gene.2008.66

Cited by 38 publications

(28 citation statements)

References 25 publications

(24 reference statements)

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“…As cryopyrin is critical to the initial nucleation step in inflammasome activation [31], reduction of its levels could account for the diminished activity of the inflammasome. Such a mechanism would be in keeping with the proposition of how inflammasomes form and the recognition that a large proportion of patients with cryopyrin-associated periodic syndrome appear to suffer from the consequence of increased expression of the components of the inflammasome, rather than an innately more active inflammasome [32]. However, we have not established that the reduced levels of cryopyrin wholly account for the reduced activity of this inflammasome, and therefore, it cannot be excluded that PKR activity regulates the expression of alternative transcripts that control this response.…”

Section: Discussionmentioning

confidence: 89%

The kinase activity of PKR represses inflammasome activity

Yim

Wang

et al. 2016

Cell Res

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The protein kinase R (PKR) functions in the antiviral response by controlling protein translation and inflammatory cell signaling pathways. We generated a transgenic, knock-in mouse in which the endogenous PKR is expressed with a point mutation that ablates its kinase activity. This novel animal allows us to probe the kinase-dependent and -independent functions of PKR. We used this animal together with a previously generated transgenic mouse that is ablated for PKR expression to determine the role of PKR in regulating the activity of the cryopyrin inflammasome. Our data demonstrate that, in contradiction to earlier reports, PKR represses cryopyrin inflammasome activity. We demonstrate that this control is mediated through the established function of PKR to inhibit protein translation of constituents of the inflammasome to prevent initial priming during innate immune signaling. These findings identify an important role for PKR to dampen inflammation during the innate immune response and caution against the previously proposed therapeutic strategy to inhibit PKR to treat inflammation.

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Section: Discussionmentioning

confidence: 89%

The kinase activity of PKR represses inflammasome activity

Yim

Wang

et al. 2016

Cell Res

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“…Several binding motifs were previously noticed for the proliferative and proinflammatory transcription factors, including SP1, c-MYB, AP-1, c-ETS (18), and recently, NF-B (25). However, the induction of NLRP3 by PXR was unlikely via these motifs because the PXR activation were known to inhibit NF-B and AP-1 both in the liver and ECs (7, 26) Instead, we found recurrent PXREs in the NLRP3 promoter and confirmed the PXR binding and activation, although the functionality of each individual motif was difficult to be dissected due to the multiplicity of the motifs.…”

Section: Discussionmentioning

confidence: 99%

Xenobiotic Pregnane X Receptor (PXR) Regulates Innate Immunity via Activation of NLRP3 Inflammasome in Vascular Endothelial Cells

Wang

Lei

Zhang

et al. 2014

Journal of Biological Chemistry

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Background: Xenobiotics activate nuclear receptor PXR for detoxification and clearance. However, a role of PXR in regulating innate immunity remains unknown. Results: PXR induced NLRP3 expression and triggered inflammasome activation in vascular ECs. Conclusion: PXR plays an important role in the activation of NLRP3 inflammasome in response to xenobiotics. Significance: Our findings revealed a novel mechanism of innate immunity.

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“…Sequence variants in the promoter region were found in a portion of these mutation-negative patients, possibly leading to enhanced gene transcription [105]. In addition, a single nucleotide polymorphism in the 3 0 UTR of NLRP3 has been shown to be linked to disease [106].…”

Section: Stimuli Activating Nlrp3mentioning

confidence: 99%

Inflammasomes: current understanding and open questions

Bauernfeind¹,

Ablasser²,

Bartok³

et al. 2010

Cell. Mol. Life Sci.

322

306

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The innate immune system relies on its capability to detect invading microbes, tissue damage, or stress via evolutionarily conserved receptors. The nucleotide-binding domain leucine-rich repeat (NLR)-containing family of pattern recognition receptors includes several proteins that drive inflammation in response to a wide variety of molecular patterns. In particular, the NLRs that participate in the formation of a molecular scaffold termed the "inflammasome" have been intensively studied in past years. Inflammasome activation by multiple types of tissue damage or by pathogen-associated signatures results in the autocatalytic cleavage of caspase-1 and ultimately leads to the processing and thus secretion of pro-inflammatory cytokines, most importantly interleukin (IL)-1β and IL-18. Here, we review the current knowledge of mechanisms leading to the activation of inflammasomes. In particular, we focus on the controversial molecular mechanisms that regulate NLRP3 signaling and highlight recent advancements in DNA sensing by the inflammasome receptor AIM2.

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Initial description of the human NLRP3 promoter

Cited by 38 publications

References 25 publications

The kinase activity of PKR represses inflammasome activity

The kinase activity of PKR represses inflammasome activity

Xenobiotic Pregnane X Receptor (PXR) Regulates Innate Immunity via Activation of NLRP3 Inflammasome in Vascular Endothelial Cells

Inflammasomes: current understanding and open questions

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