Journal Article

Distinct changes in endosomal composition promote NLRP3 inflammasome activation

Zhang, Zhirong, Vivot, Karl, Bonifacino, Juan S., Schürmann, Annette, Ricci, Romeo, Ran, Li, De Matteis, Maria Antonietta, Liu, Zengzhen, Venditti, Rossella

2023

Overview

Inflammasome complexes are pivotal in the innate immune response. The NLR family pyrin domain containing protein 3 (NLRP3) inflammasome is activated in response to a broad variety of cellular stressors. However, a primary and converging sensing mechanism by the NLRP3 receptor initiating inflammasome assembly remains ill defined. Here, we demonstrate that NLRP3 inflammasome activators primarily converge on disruption of endoplasmic reticulum–endosome membrane contact sites (EECS). This defect causes endosomal accumulation of phosphatidylinositol 4-phosphate (PI4P) and a consequent impairment of endosome-to- trans -Golgi network trafficking (ETT), necessary steps for endosomal recruitment of NLRP3 and subsequent inflammasome activation. Lowering endosomal PI4P levels prevents endosomal association of NLRP3 and inhibits inflammasome activation. Disruption of EECS or ETT is sufficient to enhance endosomal PI4P levels, to recruit NLRP3 to endosomes and to potentiate NLRP3 inflammasome activation. Mice with defects in ETT in the myeloid compartment are more susceptible to lipopolysaccharide-induced sepsis. Our study thus identifies a distinct cellular mechanism leading to endosomal NLRP3 recruitment and inflammasome activation. A dogma in the inflammasome field is that NLRP3 activation occurs at dispersed vesicles of the trans -Golgi network. Here, Ricci and colleagues find that these vesicles are of endosomal origin and that endosomes comprise the compartment where NLRP3 is activated.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/262/2106/2517 / 631/80/313/1776 / Animals / Antibodies / Biomedical and Life Sciences / Biomedicine / Carrier Proteins - metabolism / Cellular stress response / Endoplasmic reticulum / Endosomes / Endosomes - metabolism / Experiments / Golgi apparatus / Immune response / Immunity, Innate / Immunology / Infectious Diseases / Inflammasomes / Inflammasomes - metabolism / Innate immunity / Life Sciences / Lipopolysaccharides / Mice / NLR Family, Pyrin Domain-Containing 3 Protein - metabolism / Phosphatidylinositol 4-phosphate / Potassium / Protein transport / Pyrin protein / Sepsis / Vesicles