Distinct changes in endosomal composition promote NLRP3 inflammasome activation
ZHANG Z. 1,2,3,4, VENDITTI R. 5,6, RAN L. 1,2,3,4, LIU Z. 1,2,3,4, VIVOT K. 1,2,3,4, SCH▄RMANN A. 7, S. BONIFACINO J. 8, DE MATTEIS M. 5,6, RICCI R. 1,2,3,4,9
1 Institute of Genetics and Molecular and Cellular Biology (IGBMC), Illkirch, France; 2 Centre National de la Recherche Scientifique, UMR7104, Illkirch, France; 3 Institut National de la SantÚ et de la Recherche MÚdicale, U964, Illkirch, France; 4 UniversitÚ de Strasbourg, Strasbourg, France; 5 Telethon Institute of Genetics and Medicine, Pozzuoli, Italy; 6 Department of Molecular Medicine and Medical Biotechnology, University of Napoli Federico II, Medical School, Naples, Italy; 7 German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Nuthetal, Germany; 8 Neurosciences and Cellular and Structural Biology Division, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Maryland, United States; 9 Laboratoire de Biochimie et de Biologie MolÚculaire, Nouvel H˘pital Civil, Strasbourg, France
Inflammasome complexes are pivotal in the innate immune response to pathogens and other danger signals. The NLRP3 inflammasome is activated in response to a broad variety of cellular stressors. Most of the stimuli act in a potassium efflux-dependent manner but a primary and converging sensing mechanism by the NLRP3 receptor initiating inflammasome assembly remains ill-defined. In this study, through cell biological and genetic approaches, we have demonstrated that NLRP3 inflammasome activators primarily converge on disruption of ER-endosome membrane contact sites (EECS). This defect causes endosomal accumulation of PI4P and a consequent impairment of endosome-to-TGN trafficking (ETT), necessary steps for binding of NLRP3 to endosomes and subsequent inflammasome activation. Lowering endosomal PI4P levels prevents endosomal recruitment 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 LPS-induced sepsis in a NLRP3-dependent manner. Our study thus identifies a distinct cellular mechanism leading to endosomal NLRP3 recruitment and inflammasome activation.