NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain

  title={NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain},
  author={Andrea Stutz and Carl Christian Kolbe and Rainer Stahl and Gabor L Horvath and Bernardo Simoes Franklin and Olivia van Ray and Rebecca Brinkschulte and Matthias Geyer and Felix Meissner and Eicke Latz},
  journal={The Journal of Experimental Medicine},
  pages={1725 - 1736}
NLRP3 is a cytosolic pattern recognition receptor that senses microbes and endogenous danger signals. Upon activation, NLRP3 forms an inflammasome with the adapter ASC, resulting in caspase-1 activation, release of proinflammatory cytokines and cell death. How NLRP3 activation is regulated by transcriptional and posttranslational mechanisms to prevent aberrant activation remains incompletely understood. Here, we identify three conserved phosphorylation sites in NLRP3 and demonstrate that NLRP3… 

Figures from this paper

NLRP3 phosphorylation in its LRR domain critically regulates inflammasome assembly

NLRP3 S803 phosphorylation status as a druggable apical molecular mechanism controlling inflammasome assembly is revealed, with NLRP3 phosphomimetic mutants showing enhanced ubiquitination and degradation than wildtype NL RP3.

AKT Regulates NLRP3 Inflammasome Activation by Phosphorylating NLRP3 Serine 5

It is proposed that AKT, Trim31, and PP2A together modulate NLRP3 protein levels and the tendency to oligomerize, thereby setting a tightly regulated threshold forNLRP3 activation.

Regulation of NLRP3 Inflammasome by Phosphorylation

The post-translational modification of NLRP3 as well as other inflammasome components has been showed to be critical for the regulation of its activation, and interesting areas for future research are suggested.

Effects of phosphorylation on the NLRP3 inflammasome.

Priming of NLRP3 inflammasome activation by Msn kinase MINK1 in macrophages

This study reveals a direct regulation of the NLRP3 inflammasome by Msn family kinase MINK1 and suggests that modulation of Mink1 activity is a potential intervention strategy for inflammaome-related diseases.

Evaluation of protein kinase D auto-phosphorylation as biomarker for NLRP3 inflammasome activation

The promiscuous reactivity of PKD challenges its potential use for tracing the NLRP3 inflammasome pathway, and assessments of the pyrin and NLRC4 pathways revealed that PKD auto-phosphorylation can be triggered by a broad range of stimuli unrelated to NLRP2 inflammaome assembly.

Posttranslational Regulation of the NLR Family Pyrin Domain-Containing 3 Inflammasome

The role of PTMs regulating NLRP3 inflammasome activation is focused on and mechanisms related to regulation of posttranslational modification ofNLRP3, as a focal point has not been thoroughly addressed.

Acetylation is required for NLRP3 self-aggregation and full activation of the inflammasome

This study finds the second signal specially triggers the acetylation of NLRP3, which facilitates the aggregation ofNLRP3 and its interaction with ASC and NEK7, thus promoting the assembly of inflammasome.

NLRP3 Ubiquitination—A New Approach to Target NLRP3 Inflammasome Activation

The ubiquitination and deubiquitination system for NLRP3 inflammasome activation and the inhibitors that can be used as potential therapeutic agents to modulate the activation of the NLRP2 inflammaome are discussed.



NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations

It is found that Ser295 in human NLRP3 was critical for rapid inhibition and PKA phosphorylation, which is linked to the inflammatory disease CAPS (cryopyrin-associated periodic syndromes) and identify a molecular basis for CAPS-associatedNLRP3 mutations.

NLRP 3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase PTPN 22

Tyrosine phosphorylation is identified as an important regulatory mechanism for NLRP3 that prevents aberrant inflammasome activation and subsequent IL-1b release.

Cutting Edge: NF-κB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression1

It is shown that cell priming through multiple signaling receptors induces NLRP3 expression, which is identified to be a critical checkpoint for NLRP2 activation and signals provided by NF-κB activators are necessary but not sufficient forNLRP3 activation.

Non-transcriptional Priming and Deubiquitination Regulate NLRP3 Inflammasome Activation*

In mouse macrophages, signaling by the pattern recognition receptor TLR4 through MyD88 can rapidly and non-transcriptionally prime NLRP3 by stimulating its deubiquitination, which could explain how NL RP3 is activated by diverse danger signals.

Cutting Edge: Nitric Oxide Inhibits the NLRP3 Inflammasome

It is found that endogenous NO is involved in the regulation of NLRP3 inflammasome activation by either IFN-β pretreatment or long-term LPS stimulation, and S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, markedly inhibited NLRP2 and NLRC4Inflammasomes were only partially inhibited by SNAP, while an increase in mitochondrial reactive oxygen species induced by ATP was only modestly affected by SNAP treatment.

Sphingosine regulates the NLRP3-inflammasome and IL-1β release from macrophages

It is shown that the endogenous lipid metabolite sphingosine (Sph) acts as a DAMP by inducing the NLRP3‐inflammasome‐dependent secretion of IL‐1β from macrophages, and that a serine/threonine phosphatase (PP1/PP2A)‐dependent signal is central to the endogenous host mechanism through which diverse stimuli regulate inflammasomes activation.

Curcumin suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock.

This work finds that curcumin potently inhibits the activation of NLRP3 inflammasome which may contribute to its anti-inflammatory activity and offers a mechanistic basis for the therapeutic potential ofCurcumin in septic shock and other NLRP2 inflammaome-driven diseases.

AIM2 recognizes cytosolic dsDNA and forms a caspase-1 activating inflammasome with ASC

Using mouse and human cells, the PYHIN (pyrin and HIN domain-containing protein) family member absent in melanoma 2 (AIM2) is identified as a receptor for cytosolic DNA, which regulates caspase-1.