NLRP10 engages oxidized DNA through a Schiff-base mechanism and dissociates from NLRP3 upon inflammasome activation.

Julia Elise Cabral, Angela Lackner, Wenjin Jiang, Sophia Lin, Haitian Zhou, Anna Wu, Courtney Demos, Minh Anh Pham, Reginald McNulty

Laboratory of Macromolecular Structure, Department of Molecular Biology & Biochemistry, University of California, Irvine, CA, USA.Laboratory of Macromolecular Structure, Department of Molecular Biology & Biochemistry, University of California, Irvine, CA, USA. · pubmed

Paper

Abstract

Mitochondrial DNA 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 is involved in the release of D-loop mtDNA into the cytosol. We further show that NLRP3 interacts with NLRP10. NLRP10-mediated oxidized 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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Research summary

NLRP10 interacts with oxidized DNA and modulates inflammasome activation, potentially contributing to the senescence secretory phenotype. The study addresses mechanisms that could influence aging processes and innate immunity, which are relevant to longevity research.

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