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NLRP10 Cleaves Oxidized DNA inhibited by OGG1 inhibitors: A Newly Identified Role in DNA Damage Processing and
Abstract:
Mitochondrial DNA (mtDNA) release into the cytosol is a critical event in innate immune activation, often acting as a damage-associated molecular pattern (DAMP) that triggers inflammasome assembly. Here, we demonstrate that NLRP3 plays a direct role in cleaving and facilitating the release of D-loop mtDNA into the cytosol. We further show that NLRP3 interacts with NLRP10. NLRP10-mediated ox-DNA cleavage involves a Schiff base intermediate and is inhibited by small molecules known to inhibit glycosylases. These findings support a model where NLRP10 interaction with oxidized DNA may contribute to long-term senescence secretory phenotype and modulate inflammasome activation. Our study highlights a novel mechanism by which NLRP10 can respond to mitochondrial stress signals to influence innate immunity and suggests therapeutic potential for targeting these interactions in inflammatory diseases.
Insights
Mitochondrial DNA (mtDNA) release triggers innate immunity. This study reveals NLRP3 cleaves mtDNA, facilitating its release and interacting with NLRP10 to modulate inflammasome activation and inflammatory diseases.
Area of Science:
- Immunology
- Molecular Biology
- Cellular Biology
Background:
- Mitochondrial DNA (mtDNA) release into the cytosol acts as a damage-associated molecular pattern (DAMP), initiating innate immune responses and inflammasome assembly.
- The precise mechanisms governing mtDNA release and its role in inflammasome activation are still under investigation.
Purpose of the Study:
- To elucidate the direct role of NLRP3 in mitochondrial DNA (mtDNA) release and inflammasome activation.
- To investigate the interaction between NLRP3 and NLRP10 in response to mitochondrial stress.
- To explore the therapeutic potential of targeting NLRP10-mediated pathways in inflammatory diseases.
Main Methods:
- Demonstration of NLRP3's direct role in cleaving and releasing D-loop mtDNA into the cytosol.
- Investigation of the interaction between NLRP3 and NLRP10.
- Analysis of NLRP10-mediated oxidized DNA (ox-DNA) cleavage, including Schiff base intermediate identification and inhibition studies using glycosylase inhibitors.
Main Results:
- NLRP3 directly cleaves and facilitates the release of D-loop mtDNA into the cytosol.
- NLRP3 forms an interaction with NLRP10.
- NLRP10-mediated ox-DNA cleavage involves a Schiff base intermediate and is inhibited by glycosylase inhibitors, suggesting a role in senescence and inflammasome modulation.
Conclusions:
- NLRP3 plays a critical role in initiating innate immunity by cleaving and releasing mtDNA.
- NLRP10 interacts with NLRP3 and responds to mitochondrial stress signals, influencing innate immunity and potentially contributing to senescence.
- Targeting NLRP10-mtDNA interactions presents a novel therapeutic strategy for inflammatory diseases.
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