Journal Article

Inflammasome-independent NLRP3 function enforces ATM activity in response to genotoxic stress

Bodnar-Wachtel, Mélanie, Gérossier, Laetitia, Hall, Janet, Guey, Baptiste, Goutagny, Nadège, Bartosch, Birke, Truntzer, Caroline, Couté, Yohann, Burlet, Delphine, Huber, Anne-Laure, Lantuejoul, Sylvie, Ballot, Elise, Hacot, Sabine, Gorry, Julie, Py, Bénédicte F, Ballesta, Annabelle, Tissier, Agnès, Lecuelle, Julie, Petrilli, Virginie, Ghiringhelli, François

2023

Overview

NLRP3 is a pattern recognition receptor with a well-documented role in inducing inflammasome assembly in response to cellular stress. Deregulation of its activity leads to many inflammatory disorders including gouty arthritis, Alzheimer disease, and cancer. Whereas its role in the context of cancer has been mostly explored in the immune compartment, whether NLRP3 exerts functions unrelated to immunity in cancer development remains unexplored. Here, we demonstrate that NLRP3 interacts with the ATM kinase to control the activation of the DNA damage response, independently of its inflammasome activity. NLRP3 down-regulation in both broncho- and mammary human epithelial cells significantly impairs ATM pathway activation, leading to lower p53 activation, and provides cells with the ability to resist apoptosis induced by acute genotoxic stress. Interestingly, NLRP3 expression is down-regulated in non-small cell lung cancers and breast cancers, and its expression positively correlates with patient overall survival. Our findings identify a novel non-immune function for NLRP3 in maintaining genome integrity and strengthen the concept of a functional link between innate immunity and DNA damage sensing pathways to maintain cell integrity.

• Publisher: Life Science Alliance,Life Science Alliance LLC
• Subject: Alzheimer's disease / Apoptosis / Apoptosis - genetics / Ataxia Telangiectasia Mutated Proteins - genetics / Ataxia Telangiectasia Mutated Proteins - metabolism / Breast cancer / Cell activation / Cell cycle / Cell death / Cellular stress response / Datasets / DNA Damage / Down-regulation / Epithelial cells / Genomes / Genotoxicity / Humans / Immune response / Immunity, Innate / Inflammasomes / Inflammasomes - metabolism / Inflammatory diseases / Innate immunity / Kinases / Life Sciences / Mammary gland / Medical prognosis / Mutation / Neurodegenerative diseases / NLR Family, Pyrin Domain-Containing 3 Protein - genetics / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / p53 Protein / Patients / Pattern recognition receptors / Prostate / Proteins / Tumors