Non-transcriptional Priming and Deubiquitination Regulate NLRP3 Inflammasome Activation*

By Christine A. Juliana, T. Fernandes-Alnemri, Seokwon Kang, André B. Farias, F. Qin, E. Alnemri. Journal of Biological Chemistry, 2012

723 citations recorded by the source corpus.

Background: The NLRP3 inflammasome is a critical mediator of inflammation in response to pathogens, tissue damage, and metabolic diseases. Results: Non-transcriptional priming and activation signals stimulate NLRP3 deubiquitination. Conclusion: The NLRP3 inflammasome is non-transcriptionally primed and activated by a deubiquitination mechanism. Significance: Understanding the mechanism of activation of the NLRP3 inflammasome is crucial for the development of therapeutics to alleviate NLRP3-dependent inflammatory diseases. The NLRP3 inflammasome is a key component of the innate immune response to pathogenic infection and tissue damage. It is also involved in the pathogenesis of a number of human diseases, including gouty arthritis, silicosis, atherosclerosis, and type 2 diabetes. The assembly of the NLRP3 inflammasome requires a priming signal derived from pattern recognition or cytokine receptors, followed by a second signal derived from extracellular ATP, pore-forming toxins, or crystalline materials. How these two signals activate the NLRP3 inflammasome is not yet clear. Here, we show that in mouse macrophages, signaling by the pattern recognition receptor TLR4 through MyD88 can rapidly and non-transcriptionally prime NLRP3 by stimulating its deubiquitination. This process is dependent on mitochondrial reactive oxygen species production and can be inhibited by antioxidants. We further show that signaling by ATP can also induce deubiquitination of NLRP3 by a mechanism that is not sensitive to antioxidants. Pharmacological inhibition of NLRP3 deubiquitination completely blocked NLRP3 activation in both mouse and human cells, indicating that deubiquitination of NLRP3 is required for its activation. Our findings suggest that NLRP3 is activated by a two-step deubiquitination mechanism initiated by Toll-like receptor signaling and mitochondrial reactive oxygen species and further potentiated by ATP, which could explain how NLRP3 is activated by diverse danger signals.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/543d4cd4e0b4b8231184d8751c6cbe91a2c84e99

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In Immunology

1. T. Kanneganti
2. M. Lamkanfi
3. V. Dixit
4. Shao-Cong Sun
5. Ting Liu
6. Lingyun Zhang
7. Donghyun Joo
8. G. Núñez

In Molecular Biology

1. T. Kanneganti
2. M. Lamkanfi
3. G. Núñez
4. S. Man
5. Yuan He
6. V. Dixit
7. Shao-Cong Sun
8. Ting Liu

Citations in the corpus

• Redox Regulation of NLRP3 Inflammasomes: ROS as Trigger or Effector? (2015, positive): “It has been suggested that NLRP3 is activated by a two-step deubiquitination mechanism initiated by TLR signaling and mtROS (60).”
• The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation (2019, background): “Furthermore, NLRP3 is ubiquitinated in its LRR domain, and priming signals induce its deubiquitination through the deubiquitinating enzyme BRCC3 (BRCC36 in humans), which is a JAMM domain-containing Zn2+ metalloprotease, to promote NLRP3 inflammasome activation [39,44,45].”
• An update on the regulatory mechanisms of NLRP3 inflammasome activation (2021, background): “Deubiquitination of NLRP3, another key process for the licensing of NLRP3 inflammasome activation, depends on TLR4 and mitochondrial ROS (mtROS) generation.(11,12,47) Priming signals triggered through TLR4 or TLR2 stimulation leads to the induction of Abraxas brother protein 1 (ABRO1), a subunit of ”
• Mechanisms and functions of inflammasomes. (2014, background): “This alternative signal 1 is provided by TLR4 and is relayed by its adaptors MyD88, IRAK1, and IRAK4 independently of new protein synthesis (Fernandes-Alnemri et al., 2013; Juliana et al., 2012; Lin et al., 2014).”
• Mechanism and regulation of NLRP3 inflammasome activation (2016, background): “This regulation was first revealed by the finding that priming macrophages for a short time (10 min), which is not sufficient for the induction of NLRP3 expression, significantly enhances inflammasome activation [22,23].”
• Regulation of inflammasome activation (2015, background): “enzyme, leads to activation of the inflammasome (76, 77).”
• NF-κB signaling in inflammation (2017, positive): “62, 63 Typical inducers of signal 1 include microbial components, such as TLR ligands, and cytokines like TNF-α and IL-1 β , which are known to activate NF-κ B, a transcriptional activator of both NLRP3 and pro-IL-1 β genes.”
• Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders (2017, background): “LPS-induced priming could affect the ubiquitination status of NLRP3 and then regulated NLRP3 activation (Juliana et al., 2012), and we found that CY-09 had no effects on NLRP3 ubiquitination during LPS-induced priming (Fig.”
• Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome. (2016, background): “Bile Acids and TGR5 Signaling Promote NLRP3 Ubiquitination Recent studies have shown that the deubiquitination of NLRP3 is critically involved in NLRP3 inflammasome activation, whereas inhibition of NLRP3 deubiquitination blocks both mouse and human NLRP3 activation (Juliana et al., 2012; Py et al.,”
• Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. (2015, neutral): “Here, we demonstrate that DA can induce the degradation of NLRP3 protein to inhibit NLRP3 inflammasome and support the recent findings that NLRP3 ubiquitination might play an important role in the regulation of inflammasome activation (Juliana et al., 2012; Py et al., 2013).”