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NLRP10 Cleaves Oxidized DNA inhibited by OGG1 inhibitors: A Newly Identified Role in DNA Damage Processing and Senescence Regulation.

Cabral, J. E.; Lin, S.; Zhou, H.; Wu, A.; Lackner, A.; Pham, M. A.; Chi, F.; McNulty, R.

2025-03-12 immunology
10.1101/2025.03.07.642110 bioRxiv
Show 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.

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