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

## TL;DR

NLRP10 interacts with NLRP3 and cleaves oxidized mitochondrial DNA, influencing innate immunity and potentially inflammatory diseases.

## Contribution

NLRP10's DNA cleavage mechanism via a Schiff base and its dissociation from NLRP3 during inflammasome activation is newly revealed.

## Key findings

- NLRP3 is involved in releasing D-loop mtDNA into the cytosol.
- NLRP10 cleaves oxidized DNA using a Schiff base mechanism.
- NLRP10's activity may influence senescence and inflammasome activation.

## 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.

The cytosolic innate immune sensor NLRP10 interacts with NLRP3 and mediates the cleavage of oxidized mitochondrial DNA